GEP- NETS UPDATE: Genetics of neuroendocrine tumors

in European Journal of Endocrinology
Correspondence should be addressed to J Crona; Email: joakim.crona@medsci.uu.se

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel–Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

Abstract

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel–Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

Neuroendocrine tumors

Neuroendocrine tumors (NETs) are rare neoplasms originating from neuroendocrine cells most commonly located in the endocrine glands but also in the gastrointestinal and bronchopulmonary systems (Fig. 1) (1). NETs usually display slow proliferation but have a high rate of advanced stage at presentation (2, 3). Neuropeptide hypersecretion is a hallmark of these diseases and often results in distinct hormonal syndromes. These syndromes are associated with both increased morbidity and mortality (2, 4). The median survival of patients with well differentiated NETs is about 10 years, contributing to the relatively high prevalence of these diseases (5, 6).

Figure 1

Download Figure

Figure 1

Overview of genes with recurrent mutations in NETs and their distribution accordingly to anatomical location.

Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972

NET is one of the most heritable groups of neoplasms that feature in at least ten genetic syndromes. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. In this review we will present relevant genetic information regarding these diagnostic entities. We will also summarize data from tumor sequencing studies that provided comprehensive maps of the genomic landscape of NETs. Finally we comment on the current and future potential of these data as tools for the development of biomarkers as well as novel druggable targets. Below we present syndromes and additional susceptibility genes with increased risk of NET development (Table 1). The present paper reviews genetic profiles, by means of early and late mutations, of relevance for tumorigenesis in NETs.

Table 1

Genetic syndromes with NET manifestation. Overview of genetic syndromes that involve NETs; penetrance of NETs at the specified location is presented in parenthesis; figures on penetrance are presented when available.

NameGeneNET manifestationOther manifestation
MEN1MEN1Parathyroid (>90%), gastroenteropancreatic (50%), anterior pituitary (30%), lung and thymus (10%)Adrenocortical tumors
MEN2A (FMTC)RETMedullary thyroid (90–100%), adrenal medulla (20–80%), parathyroid (20%)a
MEN2BRETParathyroid, medullary thyroid (100%), adrenal medulla (50%)Marfanoid habitus
MEN4CDKN1BParathyroid, pancreas, pituitary
Neurofibromatosis type 1NF1Adrenal medulla (1–5%), duodenumNeurofibroma, cafe-au-lait spots
von Hippel–LindauVHLAdrenal medulla and sympathetic ganglia (15%), pancreas (10%)Hemangioblastoma, renal carcinoma
Familial PGL 1-5SDHA-D, SDHAF2Sympathetic and parasympathetic paraganglia, Adrenal medullaGIST, renal carcinoma
Familial PCC and PGL syndromesTMEM127, MAX, FH, MDH2Adrenal medulla, sympathetic ganglia (TMEM127 30%)
Polycytemia paranganglioma syndromeEPAS1Sympathetic ganglia, adrenal medulla, duodenumPolycytemia
Tuberous sclerosis complexesTSC1, TSC2PancreasHamartoma
HPT-JT syndromeHRPT2Parathyroid adenoma (80%) and carcinoma (15%)

Penetrance in MEN2 is specific to the particular mutation.

Genetic syndromes

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1; OMIM 131100) is one of the first described autosomal dominantly inherited complex endocrine syndromes (7). MEN1 has a high penetrance, over 90% by age 40, and is present in about three per 100 000 individuals. Gene carriers most frequently develop tumors in the parathyroid glands (95%), the anterior pituitary (20–40%), and in the endocrine cells of the pancreas/duodenum (40–80%) (8). Any of these can be the presenting lesion, and typically clinically detectable in the young adult, although rare cases of childhood tumors are reported. By definition MEN1 is present if two of these classical target tissues are affected by tumors, and familial MEN1 includes at least one relative with a corresponding tumor. Apart from the above-mentioned organs, MEN1 carriers frequently develop NETs of the foregut, e.g. bronchial, thymic, and gastric ECLomas. Adrenocortical lesions, mostly non-secreting, hyperplasias or adenomas but also rare cases of adrenocortical carcinomas are also present in MEN1 patients. The most lethal of the MEN1 lesions are the pancreatic and the thymic NETs which frequently develop into metastatic disease. Several non-endocrine tumors are also overrepresented in MEN1 patients, such as facial angiofibromas, collagenomas, lipomas and meningeomas. The typical clinical picture of the disease is highly variable between family members and dependent of the affected organs and the pattern of hypersecreted hormones in each case.

In 1988 the MEN1 gene was linked to chromosome 11q13 and suggested to be a suppressor (9). The gene was finally identified by positional cloning, and heterozygous germline inactivating MEN1 mutations was revealed in 70% of typical index cases (10). The proportion of MEN1 patients with a causative MEN1 mutation was later estimated to 75–95% (11). By now more than 1000 mutations have been recognized. The vast majority causes truncation of the protein. The most likely cases to reveal a germline MEN1 mutation are probands developing lesions at young age and show multiple tumors per organ. There is no convincing genotype–phenotype correlation identified so far. Furthermore if a mutation cannot be found it does not exclude MEN1 and recently alternative genes giving rise to syndromes resembling MEN1 have been suggested, e.g. germline CDKN1B (p27kip) mutations resulting in MEN4 (12). It have also been postulated that common genetic variants within CDKN1B could act as disease modifiers in MEN1, possibly contributing to the observed clinical heterogeneity (13).

Classical MEN1 tumorigenesis depends on a second MEN1 hit, by means of a somatic mutation eliminating also the WT allele. But some NETs in MEN1, such as thymic and duodenal NETs, do not to necessary require a complete inactivation of the gene (14). Somatic homozygous inactivation of MEN1 is also frequently seen in sporadic tumors of the MEN1 target organs.

The MEN1 protein, named menin, is ubiquitously expressed and preferentially located in the nucleus (10). It has been suggested to be a scaffold protein with more than 40 interacting proteins and thus are involved in a large number of biological functions, such as chromatin modification, DNA repair, transcription, cell division, protein degradation, motility and adhesion (15). Several Men1 knock-out mouse models mimicking the human syndrome are available.

Multiple endocrine neoplasias type 2 and familial medullary thyroid cancer

Multiple endocrine neoplasias type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) are autosomal dominantly inherited disorders characterized by development of multiple endocrine MTC, pheochromocytoma (PCC) and parathyroid adenomas (reviewed in Wells et al. (16)). MEN2 subtype A (OMIM 171400) accounts for about 80% of cases with an almost complete penetrance for MTC, while PCC and parathyroid adenoma are seen in about 50 and 30% of patients (17). MEN2B (Omim 162300) includes more aggressive MTC, dysmorphic marfanoid features but no parathyroid adenoma (18).

MEN2 and FMTC are caused by gain of function mutations in the rearranged during transfection (RET) protooncogene, localized on chromosome 10, which encodes a receptor tyrosine kinase (19, 20, 21). Gain of function mutations in RET result in autonomous activation that transduces activating signals through the RAS/MAPK and PI3K/AKT pathways (22). A majority of MEN2 and FMTC cases reveal constitutional mutations in the cysteine-rich extracellular domains (exons 10–11) of the RET gene (23), while disease causing variants within RET non-cysteine regions (exons 13–16) are less common and the related phenotype is characterized by pronounced heterogeneity (24). Patients with constitutional RET mutations show strong genotype–phenotype correlations, e.g. codon 634 transitions linked to MEN2A and codon 918 mutations linked to MEN2B. It is critical to recognize the specific RET mutation in order to optimize patient and family management, particularly for the timing of prophylactic thyroidectomy and to provide information on the risk of developing PCC and parathyroid adenoma (25, 26).

FMTC (OMIM 155240) is characterized exclusively by MTC. It has been suggested that FMTC show less aggressive disease characteristics than MTC occurring in the context of MEN2A and B (16, 27).

Multiple endocrine neoplasia type 4

Multiple endocrine neoplasia type 4 (MEN4; OMIM 610755) is a rare syndrome that is thought to predispose development of NETs, mainly parathyroid and pituitary adenomas. The trait is inherited through germline mutations in CDKN1B encoding p27kip (12). MEN4 seems to occur in an autosomal dominant fashion and is linked to loss of function mutations in the cell cycle regulator CDKN1B (12). Future studies have to be performed to confirm the phenotype and penetrance of CDKN1B mutations.

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1; OMIM 162200) is an autosomal dominant syndrome that is characterized by multiple endocrinopathies and nervous system manifestations (28). The most common features are fibromatous skin tumors, lichen eye nodules, optic gliomas and café-au-lait spots (29). Endocrinopathies are less common and include PCCs and duodenal NETs (30). Neurofibromatosis type 1 is caused by loss of function mutations in NF1 that has been linked to deregulation of both rat sarcoma viral oncogene homolog (RAS) proteins and the ERK/MAPK signaling pathway (31, 32).

von Hippel–Lindau syndrome

The von Hippel–Lindau syndrome (VHL; OMIM 193300) syndrome has an incidence of ∼1/36 000 individuals (33) and is an autosomal dominant disease. VHL is characterized by increased risk of tumors and cysts; retinal and CNS hemangioblastomas, PCC, paragangliomas (PGLs), renal clear cell carcinomas, renal cysts, pancreatic NETs, pancreatic cysts and endolymphatic sac tumors.

The syndrome is caused by inactivating mutations in the VHL tumor suppressor gene, located in 3p25 that is involved in the oxygen-sensing pathway through regulation of hypoxia-inducible factors (34). Truncation of VHL results in decreased ubiquitination of HIF transcription factors resulting in increased expression of target genes such as VEGFA etc. VHL is subclassified into type 1 (truncating mutations) and type 2 (missense mutations) that differ in clinical presentation (35). Subtype 1 presents without PCC whereas type 2 have a high penetrance of PCC. Subtype 2 may be further subclassified into type 2A without renal cell carcinoma or pancreatic cysts that may be present in subtype 2B.

PCC and PGL syndromes

There are at least 12 genes that have proved to confer susceptibility to PCCs and/or PGLs: SDHA (36), SDHB (37), SDHC (38), SDHD (39), SDHAF2 (40), FH (41), VHL (42), EPAS1 (43), NF1 (32), RET (20), TMEM127 (44) and MAX (45). The classic genetic syndromes MEN2, NF1 and VHL have been presented above. In the following section we will give an overview to more recently described diagnoses that show pronounced heterogeneity both in term of the affected organs, disease penetrance and mode of inheritance.

Familial PGL

Familial PGL syndromes types 1–5 are transmitted in an autosomal dominant manner. These syndromes are caused by the loss of function mutations in SDHD (PGL 1), SDHAF2 (PGL 2), SDHC (PGL 3), SDHB (PGL 4) and SDHA (PGL 5). SDHx genes (SDHA, SDHB, SDHC and SDHD) encode succinate dehydrogenase subunits that are catalyzing reactions in tricarboxylic acid cycle and in the respiratory electron transfer chain. Due to the disruption of the tricarboxylic acid cycle the associated PGL harbor unique metabolic profiles with accumulation of oncometabolites (46). Although familial PGL syndromes share pathogenic mechanisms, with disruption of the succinate dehydrogenase complex, the phenotype varies between the different subtypes (47). The molecular rationale for this heterogeneity remains to be identified. Paternal transmission has been shown to occur in PGL 1 and 2.

Familial PGL type 1 (OMIM 168000) have an almost complete penetrance for parasympathetic tumors in the head–neck region (48, 49). Furthermore, unilateral PCC and/or sympathetic PGLs are seen in about 25% of patients respectively (50, 51).

Familial PGL type 2 (OMIM 601650) has so far only been detected in a few European families (40, 52, 53, 54), and all reported patients have presented with parasympathetic lesions.

Familial PGL type 3 (605373) is also a rare condition that is mainly manifested by parasympathetic tumors (55, 56, 57).

Familial PGL type 4 (OMIM 115310) is associated with significant morbidity and increased mortality due to the substantial risk of development of malignant sympathetic PGLs (51, 58, 59). PCC and parasympathetic PGL also occur. In addition, patients with PGL 4 have an increased risk of developing gastrointestinal stromal tumors (GIST) as well as renal cell carcinoma (50).

Familial PGL type 5 (OMIM 614165) is associated with PCC, PGL as well as GIST. Concomitant presentation of two or more of these three tumor types seems to be exceedingly rare (36, 60, 61).

Familial PCC and PGL syndromes

Patients with familial PCC and PGL of the TMEM127 subtype (OMIM 613403) have an estimated penetrance of PCC of 30% whereas abdominal PGL are less frequent (44, 62, 63, 64). No other phenotypes have been described. This disorder presents in patients with loss of function mutations in the Transmembrane protein 127 gene that is linked to dysinhibition of the mammalian target of rapamycin (mTOR) pathway.

Myc-associated factor X (MAX) associated familial PCC and PGL (OMIM 154950) is an autosomal dominant disorder with a suggested paternal mode of transmission (45, 65). These patients show susceptibility to PCCs and PGLs with unknown penetrance. No other phenotypes have been described. This syndrome is caused by loss of function mutations in MAX that results in deregulation the MYC–MAX–MXD1 pathway (45).

Fumarate hydratase (FH) associated PCC and PGL (OMIM 136850) is an autosomal dominant syndrome previously known to result in susceptibility to leimyomatosis and renal call cancer (OMIM 150800 (66)). PCC and PGL was recently recognized as a feature of this syndrome and the penetrance is currently unknown (41, 67, 68). The syndrome is caused by function mutations in FH that results in reduced enzymatic activity with fumarate accumulation.

A recent study described germline mutations in MDH2 as a cause of PGL (69). Although this finding needs to be confirmed, it is indeed remarkable that MDH2 is the third Krebs cycle gene suggested to be involved in PGL tumorigenesis (69).

Polycytemia and PGL syndrome

Disruption of oxygen sensing is also a recurrent disease mechanism in NETs. The recently recognized polycytemia and PGL syndrome was shown to occur as a result gain of function mutations in EPAS1 that resulted in a pseudohypoxic state through reduction in HIF2α degradation mediated by disturbed VHL binding (43, 70, 71, 72). The mode of inheritance for the polycytemia and PGL syndrome (OMIM 603349) is currently unknown due to near exclusive presentation in mosaicism. These patients are prone to develop PGL, PCC, polycytemia and somatostatinoma (72). A recent study also suggested ocular manifestations in patients with polycytemia and PGL syndrome (73). A majority of patients with mosaic mutations have had female gender and the underlying mechanism for this phenomenon is unknown (72).

Tuberous sclerosis complex

Tuberous sclerosis complex subtypes 1 and 2 (OMIM 191100 and 613254) are autosomal dominant syndromes that occur in 1:6000–10 000 individuals (74, 75, 76). These patients show multiorgan manifestations; mainly hamartomas but also angiomyolipomas, renal cell carcinoma and pulmonary lymphangioleiomyomatosis (reviewed by Curatolo et al. (77)). Pancreatic NET is a less frequent manifestation (78). These syndromes are due to the loss of function mutations in TSC1 and TSC2 that encode proteins forming the tuberin–hamartin complex that is essential for mTOR signaling (79). Somatic mutations in TSC2 occur frequently in pancreatic NETs (80).

Hyperparathyroidism-jaw tumor syndrome

Hyperparathyroidism-jaw tumor syndrome (OMIM 145001) is an autosomal dominant syndrome caused by truncating mutations in the HRPT2 located on 1q31.2 (81). It is characterized by adenomatous or malignant lesions of the parathyroids, jaw tumors, as well as renal and uterine tumors (82, 83).

Genetic landscape of NETs

Compared with other tumor types the genetic landscape of NETs is characterized by relatively few mutations and chromosomal aberrations per tumor (Fig. 2). So far, around 24 genes have been associated with neuroendocrine tumorigenesis (Table 2). These genes seem to interconnect to important pathways involved in cell metabolism, chromatin modification and growth control (Fig. 3).

Figure 2

Download Figure

Figure 2

Overview of mutational burden in NETs merged from raw data in (80, 85, 86, 87, 98, 99, 100, 104, 117, 120, 121, 122, 128, 136, 137). Each dot represents a unique tumor, and the line shows the median number of mutations of each category. PT, parathyroid.

Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972

Table 2

List of genes involved in neuroendocrine tumorigenesis. Overview of genes involved in NET tumorigenesis. ALT, alternative lengthening of telomeres.

GeneGene functionChronological classificationOrgan specificity
ATMChromatin integrityUnknownPancreas
ATRXALTLatePancreas, adrenal medulla, paraganglia
CDKN1BCell cycleUnknownPancreas, small intestine, parathyroid, anterior pituitary
DAXXALTLatePancreas
EPAS1Cell signalingEarlyParaganglia, adrenal medulla, duodenum
H-, K-RASCell signalingEarlyThyroid C-cell, adrenal medulla
FHMetabolismEarlyAdrenal medulla, paraganglia
KTMD2Chromatin modificationUnknownAdrenal medulla
MAXCell signalingEarlyParaganglia, adrenal medulla
MDH2MetabolismUnknownParaganglia
MEN1UnknownEarlyParathyroid, anterior pituitary, endocrine cells in pancreas, duodenum, gastrium, lung, thymus
NF1Cell signalingEarlyAdrenal medulla, duodenum
RETCell signalingEarlythyroid C-cell, adrenal medulla, parathyroid
SDHxMetabolismEarlyParaganglia, adrenal medulla
TERT promoterTelomere maintenanceLateParaganglia
TMEM127Cell signalingEarlyParaganglia, adrenal medulla
TP53Chromatin integrity, Cell signalingUnknownEndocrine pancreas, adrenal medulla
TSC1-2Cell signalingUnknownPancreas
YY1Transcriptional regulationEarlyPancreas
Figure 3

Download Figure

Figure 3

Simplified overview of genes and pathways involved in NET tumorigenesis.

Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972

Parathyroid adenoma and carcinoma

Constitutional mutations in CDC73 (81), MEN1 (84), RET (20) and possibly CDKN1B (12) and CASR (83) cause susceptibility to parathyroid adenoma. Two exome sequencing studies investigated the genomic landscape of parathyroid adenomas and discovered somatic MEN1 mutations in 35% of cases (85, 86). A third study investigated the exomes of parathyroid carcinomas identified recurrent mutations in the PRUNE2 gene (87). The median number of somatic amino acid substituting mutations per adenoma was eight (range 2–100) (86). Parathyroid carcinomas harbored more mutations (synonymous average 51, range 3–176) that showed an apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) like mutational signature (87). APOBEC associated genomic instability is a result of cytosine-to-uracil deamination that is catalyzed by APOBEC3A-H enzymes and have been shown to occur in multiple different types of carcinomas (88).

Gastric, duodenal and pancreatic NETs

Constitutional mutations in MEN1 (84), VHL (42), NF1 (32), EPAS1 (somatostatinoma) (43), as well as TSC1 and 2 (74, 75) cause susceptibility to pancreatic NETs. CDKN1B have also been suggested as a susceptibility locus, but limited numbers of cases have been presented (12). In sporadic pancreatic NETs ATRX, DAXX, MEN1, TP53, ATM and mTOR pathway related genes are commonly mutated in a somatic fashion (80, 89, 90, 91). Pancreatic NETs harboring somatic mutations in ATRX and DAXX have been associated with chromosomal instability and reduced survival (92). It has been suggested that ATRX and DAXX mutations are not involved in the initial phase of tumorigenesis. Instead these mutations are thought to be late events that result in malignant transformation of PNETs (92, 93). The proposed pathogenic mechanism of ATRX and DAXX deficiency is the activation of the alternative lengthening of telomeres phenotype (94, 95). This phenotype has been associated with genome rearrangements, defects in the G2/M checkpoint and altered double-strand break repair (95). It have also been suggested that ATRX/DAXX mutations lead to differential epigenetic deregulation (96). The mean number of amino acid substituting somatic mutations in non-functioning pancreatic NETs were 16 (80). The degree of chromosomal aberrations is more variable and ranges from no somatic copy number alterations to genome-wide aneuploidy (92, 97).

Insulin producing pancreatic NETs with manifest hypoglycemic symptoms, i.e. insulinomas, have been identified with recurrent somatic mutations in YY1. This gene encodes a nuclear transcription factor and the described recurrent mutation Thr372Arg has been shown to result in neomorphic effects and altered transcription (98, 99, 100). Insulinomas exhibit a low mutational burden and the average amino acid substituting mutations were four per tumor (98, 99, 100). High chromosomal instability has been recognized in a subset of insulinomas especially in those with malignant features (101).

Although limited studies have been presented, evidence indicates that the genetics of duodenal and gastric NETs overlap with the profile observed in pancreatic NETs (90, 102).

Medullary thyroid carcinoma

Germline mutations in RET cause MEN 2 and FMTC; both syndromes showing high penetrance of MTC (20). MTC from MEN2 patients rarely show any other somatic driver mutations (103). Investigating the genomic landscape of sporadic MTCs revealed mutually exclusive oncogenic mutations in RET and RAS subtypes K and H in 75 and 15% respectively (104, 105, 106). Furthermore there were an average of 18 amino acid substituting somatic mutations per MTC (104). ALK gene fusions were recently described in two out of 98 investigated cases suggesting that ALK inhibition might further be evaluated for treatment of these rare tumors (107, 108).

PCC and PGLs

Mutations in up to 20 genes have been suggested with PCC and PGL tumorigenesis. A total of 12 genes is believed cause of genetic susceptibility to PCC and PGL and a further six loci have been suggested but remains to be validated. These include KIF1Bβ (109, 110), IDH1 (111), MDH2 (69), BAP1 (112) as well as EGLN subtypes 1 and 2 (113, 114). Somatic mutations in HRAS have been shown to cause these diseases (115, 116). Several genes have also been suggested to work as the disease modifiers of PCC and PGL. ATRX have been identified in a subset of malignant PCC and PGL having the alternative lengthening of telomeres phenotype (117). TERT promoter mutations have been identified to occur exclusively in succinate dehydrogenase deficient PGL (118, 119). A recent study also described the recurrent somatic mutations in KMT2D. Whether this gene acts as a disease driver or modifier remains to be identified (120). The genomic landscape of PCC and PGL is associated with relatively low degree of genomic instability having an average of 19 non-synonymous mutations per tumor (117, 121, 122). Clinical criteria have classified these tumors accordingly to location into PCCs (adrenal medulla) and PGLs (extra adrenal). Accumulating evidence show that it is possible to sub-classify PCC and PGL into at least three distinct molecular clusters (based on methylome, transcriptome and siRNAome) having unique mutational profiles as well as different clinical characteristics (41, 121, 123). Cluster 1a is enriched with noradrenaline producing PGLs that show mutations in genes involved in cell metabolism through the Kreb cycle (SDHX, FH and MDH2) (121). Cluster 1b has noradrenaline producing PCC and PGL with a pseudohypoxic phenotype (VHL and EPAS1) (43, 123). Cluster 2 has PCC and PGLs with a mixed adrenaline/noradrenaline phenotype having aberrantly activated signaling in the MAPK and PI3K/AKT signaling pathways (RET, NF1, TMEM127, MAX and HRAS) (45, 115, 124, 125) (Fig. 4)

Figure 4

Download Figure

Figure 4

Theory of evolution, with relevant driver genes, in NET tumorigenesis. The 15 genes involved in pheochromocytoma and PGL tumorigenesis are: SDHx, SDHAF2, MDH2, VHL, EPAS1, NF1, RET, HRAS, TMEM127, MAX, KIF1B and KMT2D.

Citation: European Journal of Endocrinology 174, 6; 10.1530/EJE-15-0972

.

NETs of the lung

This section describes the genomic findings of well differentiated NETs derived from the broncopulmonary system. These have classically been denoted typical and atypical pulmonary carcinoids based on morphological criteria (126). Pulmonary carcinoids occur in about 5% of MEN1 patients (127). One study examining genome-wide mutation status in 44 sporadic pulmonary carcinoids identified three genes with recurrent mutations: MEN1, PSIP1 and ARID1A (128). Network analysis of genes with somatic mutations extended the number of cases with relevant mutations, 40% had covalent histone modifiers and 22% subunits of the SWI/SNF complex (22%) (128). The occurrence of somatic MEN1 mutations in sporadic pulmonary carcinoids have previously been highlighted (129). There were the averages of 13 protein-altering mutations per sample (128). Differential expression of miRNAs in typical vs atypical lung carcinoids has also been reported (130).

Thymic carcinoid

NET of the thymus is a part of MEN1 syndrome with a penetrance of <10% (8). CGH analysis found recurrent copy number alterations with the most commonly disturbance identified being gain of 8q24 (MYC locus) (131). Mutational screening of tumor tissue has been performed on a per case-basis with the finding of a few somatic MEN1 mutations (132).

Small intestinal NETs

Small intestinal NETs (SI-NETs) have also been described to occur with familial aggregation in a small fraction of patients (133, 134). Despite substantial efforts no definitive genetic basis for this phenomenon has been described. A recent study used linkage analysis and exome sequencing that revealed IPMK germline mutations in a single family (135). Although experimental investigations seem to indicate a pathogenic effect of the IPMK mutation a validation effort that included 32 additional families did not reveal the presence of any additional mutations (135). Thus IPMK inactivation is not likely to be a significant cause of familial SI-NET. The genomic landscape of SI-NETs has been investigated with exome coverage in close to 100 tumor samples (136, 137). Recurrent mutations were only identified in the CDKN1B gene with a mutation prevalence of 9% of SI-NET patients (136, 137, 138). Instead, the most frequent genomic alteration is hemizygous deletions affecting chromosome 18q (133, 136, 137, 139). Recent data have shown that SI-NETs can be sub-classified based on tumor methylome into three distinct clusters (140, 141). Sub classification of SI-NETs based on gene expression may also provide relevant information (142).

Genetic heterogeneity and tumor evolution

As clinicians seek to select treatments based on genetic biomarkers, knowledge of spatial and temporal heterogeneity could be important and should be researched further. Indeed genetic heterogeneity within and between paired tumors has been described in most NET types. Consistent with the theoretical assumption that MEN1 patients experience parallel development of independent NET clones, studies using loss of heterozygosity (LOH) LOH markers were able to show that paired tumors from MEN1 patients have unique genetic compositions (143, 144). In contrast, X-chromosome inactivation studies of sporadic parathyroid adenomas, gastrinomas, gastric-NETs and MTCs indicate that these tumors develop in a monoclonal fashion (145, 146, 147, 148). Multiple intestinal tumor lesions have been observed in about 20% of SI-NET patients (149). Whether these are the consequences of independent tumor formation or metastatic spread remain to be settled (144, 145). Recent studies highlighted that a subset of SI-NETs show pronounced genetic heterogeneity within and between tumor lesions (136, 138). Korpershoek et al. (150) determined, by using LOH markers, that there is genetic heterogeneity within different areas of selected PCCs and PGLs. Furthermore they recognized that adrenal medullary hyperplasia in MEN2 patients is in fact a precursor lesion for PPGL (151). Widespread genetic heterogeneity within these tumors as well as and between paired lesions has been recently shown (152). Of particular notice was the observed differences between paired primary and metastatic tumor lesions as well as indication of parallel evolution of different metastatic clones (152).

Authors perspectives and future implications

Precision medicine, where the unique properties of patients and tumors are used to tailor diagnostic and therapeutic procedures is now the standard of care of selected cancer types. For instance in carcinomas of the lung and gastrointestinal system knowledge of tumor mutation status is used to predict the response of treatment and detect the emergence of resistance during treatment with kinase signaling inhibitors (153, 154). The concept of precision medicine has also been useful in the management of patients with NETs, mainly for identification of those with genetic syndromes, enabling genetic counseling followed by appropriate diagnostic measures. However, knowledge of tumor mutation status is not yet used on a routine basis in NETs. Ongoing research is currently investigating whether specific RET mutations could predict the success of treatment with receptor kinase inhibitors (NCT01945762) in MTC. Another hypothesis that needs to be tested is that mutations in genes involved in mTOR signaling could be used as biomarkers of rapalogue response (155, 156).

Recent times also saw the publication of experimental findings in NETs that could be important for the development of future therapies: both combination therapy with FAK and mTOR inhibitors (157) as well as inhibition of B-catenin in MEN1 deficient pancreatic NETs (158). Immunotherapy is also an emerging branch in cancer treatment where the knowledge of tumor genetics and biology has proved to be important for prediction. Through determination of the degree of genomic instability and the neo-antigen immunoreactivity the success of PD-1 and CTLA-4 blockade may be estimated (159, 160). On the experimental level mapping the unique somatic mutations present in a particular tumor can also be used to design personalized tumor vaccination protocols (161). Furthermore, genetic instability could be targeted in ATRX or DAXX mutated tumors as they harbor the unique alternative lengthening of telomeres phenotype. Recent experimental data suggest that such tumors are sensitive to ATR inhibition (162).

However hypotheses based on extrapolation of data from basic NET research needs to be thoroughly tested in a clinical setting. There is an on-going debate whether currently available NET models are representative for human NET disease, supported by the discrepancies of the genomic landscape between NETs and commonly used cell lines (163, 164). Interpretation of basic science data must therefore be made with caution.

In order to screen for genetic disturbances in the established NET genes in a cost effective manner, reliable protocols for novel deep sequencing techniques should be implemented (165, 166). These techniques could also facilitate improvement of diagnostic yield of patients with suspicion of heritable disease. It has also been proposed that deep sequencing can improve the sensitivity in the detection of somatic mutations, especially in scenarios with a low tumor cell fraction (167). Current strategies to analyze tumor genomes are limited by the need of sufficient amount of good quality tumor tissue. In the future peripheral blood samples (liquid biopsies) containing either circulating tumor cells or circulating cell free DNA might instead be used for recognition of the genomic landscape of the individual tumors (168, 169).

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.

Funding

Our research is supported by Lions Cancerforskningsfond Uppsala and Swedish Cancer Foundation. Joakim Crona holds a research position funded by Akademiska Sjukhuset.

Acknowledgements

We thank Professor Peter Stålberg for his valuable suggestions and comments.

References

  • 1

    ModlinIMObergKChungDCJensenRTde HerderWWThakkerRVCaplinMDelle FaveGKaltsasGAKrenningEP. Gastroenteropancreatic neuroendocrine tumours. Lancet. Oncology200896172. (doi:10.1016/S1470-2045(07)70410-2).

  • 2

    EkebladSSkogseidBDunderKObergKErikssonB. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clinical Cancer Research20081477987803. (doi:10.1158/1078-0432.CCR-08-0734).

  • 3

    NorlenOStalbergPObergKErikssonJHedbergJHessmanOJansonETHellmanPAkerstromG. Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World Journal of Surgery20123614191431. (doi:10.1007/s00268-011-1296-z).

  • 4

    GrandeECapdevilaJBarriusoJAnton-AparicioLCastellanoD. Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist?Cancer Metastasis Reviews2012314753. (doi:10.1007/s10555-011-9328-6).

  • 5

    HalletJLawCHCukierMSaskinRLiuNSinghS. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer2015121589597. (doi:10.1002/cncr.29099).

  • 6

    YaoJCHassanMPhanADagohoyCLearyCMaresJEAbdallaEKFlemingJBVautheyJNRashidA. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology20082630633072. (doi:10.1200/JCO.2007.15.4377).

  • 7

    WermerP. Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine195416363371. (doi:10.1016/0002-9343(54)90353-8).

  • 8

    BrandiMLGagelRFAngeliABilezikianJPBeck-PeccozPBordiCConte-DevolxBFalchettiAGheriRGLibroiaA. Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism20018656585671. (doi:10.1210/jcem.86.12.8070).

  • 9

    LarssonCSkogseidBObergKNakamuraYNordenskjoldM. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature19883328587. (doi:10.1038/332085a0).

  • 10

    ChandrasekharappaSCGuruSCManickamPOlufemiSECollinsFSEmmert-BuckMRDebelenkoLVZhuangZLubenskyIALiottaLA. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science1997276404407. (doi:10.1126/science.276.5311.404).

  • 11

    ThakkerRV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology2014386215. (doi:10.1016/j.mce.2013.08.002).

  • 12

    PellegataNSQuintanilla-MartinezLSiggelkowHSamsonEBinkKHoflerHFendFGrawJAtkinsonMJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. PNAS20061031555815563. (doi:10.1073/pnas.0603877103).

  • 13

    LonguiniVCLourencoDMJrSekiyaTMeirellesOGoncalvesTDCoutinhoFLFranciscoGOsakiLHChammasRAlvesVA. Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. European Journal of Endocrinology/European Federation of Endocrine Societies2014171335342. (doi:10.1530/EJE-14-0130).

  • 14

    AnlaufMPerrenAHenoppTRudolfTGarbrechtNSchmittARaffelAGimmOWeiheEKnoefelWT. Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions. Gut200756637644. (doi:10.1136/gut.2006.108910).

  • 15

    AgarwalSK. Multiple endocrine neoplasia type 1. Frontiers of Hormone Research201341115. (doi:10.1159/000345666).

  • 16

    WellsSAJrPaciniFRobinsonBGSantoroM. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. Journal of Clinical Endocrinology and Metabolism20139831493164. (doi:10.1210/jc.2013-1204).

  • 17

    SteinerALGoodmanADPowersSR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type 2. Medicine196847371409. (doi:10.1097/00005792-196809000-00001).

  • 18

    MorrisonPJNevinNC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann–Froboese syndrome). Journal of Medical Genetics199633779782. (doi:10.1136/jmg.33.9.779).

  • 19

    Donis-KellerHDouSChiDCarlsonKMToshimaKLairmoreTCHoweJRMoleyJFGoodfellowPWellsSAJr. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics19932851856. (doi:10.1093/hmg/2.7.851).

  • 20

    MulliganLMKwokJBHealeyCSElsdonMJEngCGardnerELoveDRMoleSEMooreJKPapiL. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature1993363458460. (doi:10.1038/363458a0).

  • 21

    SippleJ. The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine196131163166. (doi:10.1016/0002-9343(61)90234-0).

  • 22

    WellsSAJrSantoroM. Targeting the RET pathway in thyroid cancer. Clinical Cancer Research20091571197123. (doi:10.1158/1078-0432.CCR-08-2742).

  • 23

    PonderBA. The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome. Cancer Research1999591736s1741s; discussion 1742s.

  • 24

    MukherjeeSZakalikD. RET codon 804 mutations in multiple endocrine neoplasia 2: genotype–phenotype correlations and implications in clinical management. Clinical Genetics201179116. (doi:10.1111/j.1399-0004.2010.01453.x).

  • 25

    KloosRTEngCEvansDBFrancisGLGagelRFGharibHMoleyJFPaciniFRingelMDSchlumbergerM. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid200919565612. (doi:10.1089/thy.2008.0403).

  • 26

    ChenHSippelRSO'DorisioMSVinikAILloydRVPacakK. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas201039775783. (doi:10.1097/MPA.0b013e3181ebb4f0).

  • 27

    FarndonJRLeightGSDilleyWGBaylinSBSmallridgeRCHarrisonTSWellsSAJr. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. British Journal of Surgery198673278281. (doi:10.1002/bjs.1800730411).

  • 28

    Crowe F Schull W Neel J. A Clinical Pathologicala and Genetic Study of Multiple Neurofibromatosis. Springfield IL: Charles C Thomas 1956

  • 29

    McGaughranJMHarrisDIDonnaiDTeareDMacLeodRWesterbeekRKingstonHSuperMHarrisREvansDG. A clinical study of type 1 neurofibromatosis in north west England. Journal of Medical Genetics199936197203.

  • 30

    GriffithsDFWilliamsGTWilliamsED. Duodenal carcinoid tumours, phaeochromocytoma and neurofibromatosis: islet cell tumour, phaeochromocytoma and the von Hippel–Lindau complex: two distinctive neuroendocrine syndromes. Quarterly Journal of Medicine198764769782.

  • 31

    MartinGAViskochilDBollagGMcCabePCCrosierWJHaubruckHConroyLClarkRO'ConnellPCawthonRM. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell199063843849. (doi:10.1016/0092-8674(90)90150-D).

  • 32

    WallaceMRMarchukDAAndersenLBLetcherROdehHMSaulinoAMFountainJWBreretonANicholsonJMitchellAL. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science1990249181186. (doi:10.1126/science.2134734).

  • 33

    MaherERIseliusLYatesJRLittlerMBenjaminCHarrisRSampsonJWilliamsAFerguson-SmithMAMortonN. Von Hippel–Lindau disease: a genetic study. Journal of Medical Genetics199128443447. (doi:10.1136/jmg.28.7.443).

  • 34

    Nordstrom-O'BrienMvan der LuijtRBvan RooijenEvan den OuwelandAMMajoor-KrakauerDFLolkemaMPvan BrusselAVoestEEGilesRH. Genetic analysis of von Hippel–Lindau disease. Human Mutation201031521537. (doi:10.1002/humu.21219).

  • 35

    ChenFKishidaTYaoMHustadTGlavacDDeanMGnarraJROrcuttMLDuhFMGlennG. Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype. Human Mutation199556675. (doi:10.1002/humu.1380050109).

  • 36

    BurnichonNBriereJJLibeRVescovoLRiviereJTissierFJouannoEJeunemaitreXBenitPTzagoloffA. SDHA is a tumor suppressor gene causing paraganglioma. Human Molecular Genetics20101930113020. (doi:10.1093/hmg/ddq206).

  • 37

    AstutiDLatifFDallolADahiaPLDouglasFGeorgeESkoldbergFHusebyeESEngCMaherER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics2001694954. (doi:10.1086/321282).

  • 38

    NiemannSMullerU. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics200026268270. (doi:10.1038/81551).

  • 39

    BaysalBEFerrellREWillett-BrozickJELawrenceECMyssiorekDBoschAvan der MeyATaschnerPERubinsteinWSMyersEN. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science2000287848851. (doi:10.1126/science.287.5454.848).

  • 40

    HaoHXKhalimonchukOSchradersMDephoureNBayleyJPKunstHDevileePCremersCWSchiffmanJDBentzBG. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science200932511391142. (doi:10.1126/science.1175689).

  • 41

    LetouzeEMartinelliCLoriotCBurnichonNAbermilNOttolenghiCJaninMMenaraMNguyenATBenitP. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell2013210018300189. (doi:10.1016/j.ccr.2013.04.018).

  • 42

    LatifFToryKGnarraJYaoMDuhFMOrcuttMLStackhouseTKuzminIModiWGeilL. Identification of the von Hippel–Lindau disease tumor suppressor gene. Science199326013171320. (doi:10.1126/science.8493574).

  • 43

    ZhuangZYangCLorenzoFMerinoMFojoTKebebewEPopovicVStratakisCAPrchalJTPacakK. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. New England Journal of Medicine2012367922930. (doi:10.1056/NEJMoa1205119).

  • 44

    QinYYaoLKingEEBuddavarapuKLenciREChocronESLechleiterJDSassMAroninNSchiaviF. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nature Genetics201042229233. (doi:10.1038/ng.533).

  • 45

    Comino-MendezIGracia-AznarezFJSchiaviFLandaILeandro-GarciaLJLetonRHonradoERamos-MedinaRCaroniaDPitaG. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genetics201143663667. (doi:10.1038/ng.861).

  • 46

    RichterSPeitzschMRapizziELendersJWQinNde CubasAASchiaviFRaoJUBeuschleinFQuinklerM. Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. Journal of Clinical Endocrinology and Metabolism20149939033911. (doi:10.1210/jc.2014-2151).

  • 47

    WelanderJSoderkvistPGimmO. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer201118R253R276. (doi:10.1530/ERC-11-0170).

  • 48

    van der MeyAGMaaswinkel-MooyPDCornelisseCJSchmidtPHvan de KampJJ. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet1989212911294. (doi:10.1016/S0140-6736(89)91908-9).

  • 49

    BurnichonNRohmerVAmarLHermanPLeboulleuxSDarrouzetVNiccoliPGaillardDChabrierGChabolleF. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. Journal of Clinical Endocrinology and Metabolism20099428172827. (doi:10.1210/jc.2008-2504).

  • 50

    NeumannHPPawluCPeczkowskaMBauschBMcWhinneySRMuresanMBuchtaMFrankeGKlischJBleyTA. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association2004292943951. (doi:10.1001/jama.292.8.943).

  • 51

    van HulsteijnLTDekkersOMHesFJSmitJWCorssmitEP. Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. Journal of Medical Genetics20122525. (doi:10.1136/jmedgenet-2012-101192).

  • 52

    van BaarsFCremersCvan den BroekPGeertsSVeldmanJ. Genetic aspects of nonchromaffin paraganglioma. Human Genetics198260305309. (doi:10.1007/BF00569208).

  • 53

    BayleyJPKunstHPCasconASampietroMLGaalJKorpershoekEHinojar-GutierrezATimmersHJHoefslootLHHermsenMA. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet. Oncology201011366372. (doi:10.1016/S1470-2045(10)70007-3).

  • 54

    CaseyRGarrahyATuthillAO'HalloranDJoyceCCaseyMBO'SheaPBellM. Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation. Journal of Clinical Endocrinology and Metabolism201499E1392E1396. (doi:10.1210/jc.2013-4536).

  • 55

    NiemannSSteinbergerDMullerU. PGL3, a third, not maternally imprinted locus in autosomal dominant paraganglioma. Neurogenetics19992167170. (doi:10.1007/s100480050078).

  • 56

    HensenEFvan DuinenNJansenJCCorssmitEPTopsCMRomijnJAVriendsAHvan der MeyAGCornelisseCJDevileeP. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clinical Genetics201281284288. (doi:10.1111/j.1399-0004.2011.01653.x).

  • 57

    MannelliMErcolinoTGiacheVSimiLCiramiCParentiG. Genetic screening for pheochromocytoma: should SDHC gene analysis be included?Journal of Medical Genetics200744586587. (doi:10.1136/jmg.2007.051045).

  • 58

    Gimenez-RoqueploAPFavierJRustinPRieublandCCrespinMNauVKhau Van KienPCorvolPPlouinPFJeunemaitreX. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Research20036356155621.

  • 59

    BogdasarianRLotzP. Multiple simultaneous paragangliomas of the head and neck in association with multiple retroperitoneal pheochromocytomas. Otolaryngology – Head and Neck Surgery197987648652.

  • 60

    KorpershoekEFavierJGaalJBurnichonNvan GesselBOudijkLBadoualCGadessaudNVenisseABayleyJP. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. Journal of Clinical Endocrinology and Metabolism201196E1472E1476. (doi:10.1210/jc.2011-1043).

  • 61

    PantaleoMAAstolfiAIndioVMooreRThiessenNHeinrichMCGnocchiCSantiniDCatenaFFormicaS. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. Journal of the National Cancer Institute2011103983987. (doi:10.1093/jnci/djr130).

  • 62

    YaoLSchiaviFCasconAQinYInglada-PerezLKingEEToledoRAErcolinoTRapizziERickettsCJ. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. Journal of the American Medical Association201030426112619. (doi:10.1001/jama.2010.1830).

  • 63

    AbermilNGuillaud-BatailleMBurnichonNVenisseAManivetPGuignatLDruiDChupinMJosseaumeCAffresH. TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. Journal of Clinical Endocrinology and Metabolism201297E805E809. (doi:10.1210/jc.2011-3360).

  • 64

    ToledoSPLourencoDMJrSekiyaTLuconAMBaenaMECastroCCBortolottoLAZerbiniMCSiqueiraSAToledoRA. Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation. Journal of Clinical Endocrinology and Metabolism2015100E308E318. (doi:10.1210/jc.2014-2473).

  • 65

    BurnichonNCasconASchiaviFPaes MoralesNComino-MendezIAbermilNInglada-PerezLde CubasAAAmarLBarontiniMB. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research20121828282837. (doi:10.1158/1078-0432.CCR-12-0160).

  • 66

    SmitDLMensenkampARBadeloeSBreuningMHSimonMEvan SpaendonckKYAalfsCMPostJGShanleySKrapelsIP. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clinical Genetics2011794959. (doi:10.1111/j.1399-0004.2010.01486.x).

  • 67

    ClarkGRSciacovelliMGaudeEWalshDMKirbyGSimpsonMATrembathRCBergJNWoodwardERKinningE. Germline FH mutations presenting with pheochromocytoma. Journal of Clinical Endocrinology and Metabolism201499E2046E2050. (doi:10.1210/jc.2014-1659).

  • 68

    Castro-VegaLJBuffetADe CubasAACasconAMenaraMKhalifaEAmarLAzrielSBourdeauIChabreO. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Human Molecular Genetics20142324402446. (doi:10.1093/hmg/ddt639).

  • 69

    CasconAComino-MendezICurras-FreixesMde CubasAAContrerasLRichterSPeitzschMMancikovaVInglada-PerezLPerez-BarriosA. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. Journal of the National Cancer Institute2015107Article ID: djv053doi:10.1093/jnci/djv053).

  • 70

    LorenzoFRYangCNg Tang FuiMVankayalapatiHZhuangZHuynhTGrossmannMPacakKPrchalJT. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. Journal of Molecular Medicine201291507512. (doi:10.1007/s00109-012-0967-z).

  • 71

    Comino-MendezIde CubasAABernalCAlvarez-EscolaCSanchez-MaloCRamirez-TortosaCLPedrinaciSRapizziEErcolinoTBerniniG. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Human Molecular Genetics20132221692176. (doi:10.1093/hmg/ddt069).

  • 72

    PacakKJochmanovaIProdanovTYangCMerinoMJFojoTPrchalJTTischlerASLechanRMZhuangZ. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. Journal of Clinical Oncology20133116901698. (doi:10.1200/JCO.2012.47.1912).

  • 73

    PacakKChewEYPappoASYangCLorenzoFRWilsonMWAronowMBYoungJAPopovicVZhuangZ. Ocular manifestations of hypoxia-inducible factor-2α paraganglioma-somatostatinoma-polycythemia syndrome. Ophthalmology201412122912293. (doi:10.1016/j.ophtha.2014.06.019).

  • 74

    van SlegtenhorstMde HoogtRHermansCNellistMJanssenBVerhoefSLindhoutDvan den OuwelandAHalleyDYoungJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science1997277805808. (doi:10.1126/science.277.5327.805).

  • 75

    Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell19937513051315. (doi:10.1016/0092-8674(93)90618-Z).

  • 76

    OsborneJPFryerAWebbD. Epidemiology of tuberous sclerosis. Annals of the New York Academy of Sciences1991615125127. (doi:10.1111/j.1749-6632.1991.tb37754.x).

  • 77

    CuratoloPBombardieriRJozwiakS. Tuberous sclerosis. Lancet2008372657668. (doi:10.1016/S0140-6736(08)61279-9).

  • 78

    DworakowskaDGrossmanAB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocrine-Related Cancer2009164558. (doi:10.1677/ERC-08-0142).

  • 79

    InokiKLiYZhuTWuJGuanKL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology20024648657. (doi:10.1038/ncb839).

  • 80

    JiaoYShiCEdilBHde WildeRFKlimstraDSMaitraASchulickRDTangLHWolfgangCLChotiMA. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science201133111991203. (doi:10.1126/science.1200609).

  • 81

    CarptenJDRobbinsCMVillablancaAForsbergLPresciuttiniSBailey-WilsonJSimondsWFGillandersEMKennedyAMChenJD. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genetics200232676680. (doi:10.1038/ng1048).

  • 82

    JacksonCENorumRABoydSBTalposGBWilsonSDTaggartRTMalletteLE. Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery199010810061012; discussion 1012-1003.

  • 83

    PollakMRBrownEMChouYHHebertSCMarxSJSteinmannBLeviTSeidmanCESeidmanJG. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell19937512971303. (doi:10.1016/0092-8674(93)90617-Y).

  • 84

    LemmensIVan de VenWJKasKZhangCXGiraudSWautotVBuissonNDe WitteKSalandreJLenoirG. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Human Molecular Genetics1997611771183. (doi:10.1093/hmg/6.7.1177).

  • 85

    CromerMKStarkerLFChoiMUdelsmanRNelson-WilliamsCLiftonRPCarlingT. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. Journal of Clinical Endocrinology and Metabolism201297E1774E1781. (doi:10.1210/jc.2012-1743).

  • 86

    NeweyPJNesbitMARimmerAJAttarMHeadRTChristiePTGorvinCMStechmanMGregoryLMihaiR. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. Journal of Clinical Endocrinology and Metabolism201297E1995E2005. (doi:10.1210/jc.2012-2303).

  • 87

    YuWMcPhersonJRStevensonMvanEijkRHengHLNeweyPGanARuanoDHuangDPoonSL. Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. Journal of Clinical Endocrinology and Metabolism2015100E360E364. (doi:10.1210/jc.2014-3238).

  • 88

    BurnsMBTemizNAHarrisRS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics201345977983. (doi:10.1038/ng.2701).

  • 89

    PerrenAKomminothPSaremaslaniPMatterCFeurerSLeesJAHeitzPUEngC. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. American Journal of Pathology200015710971103. (doi:10.1016/S0002-9440(10)64624-X).

  • 90

    ZhuangZVortmeyerAOPackSHuangSPhamTAWangCParkWSAgarwalSKDebelenkoLVKesterM. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Research19975746824686.

  • 91

    SadanandamAWullschlegerSLyssiotisCAGrotzingerCBarbiSBersaniSKornerJWafyIMafficiniALawlorRT. A cross-species analysis in pancreatic neuroendocrine tumors reveals molecular subtypes with distinctive clinical, metastatic, developmental, and metabolic characteristics. Cancer Discovery2015512961313. (doi:10.1158/2159-8290.CD-15-0068).

  • 92

    MarinoniIKurrerASVassellaEDettmerMRudolphTBanzVHungerFPasquinelliSSpeelEJPerrenA. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology2014146453460.e455. (doi:10.1053/j.gastro.2013.10.020).

  • 93

    de WildeRFHeaphyCMMaitraAMeekerAKEdilBHWolfgangCLEllisonTASchulickRDMolenaarIQValkGD. Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Modern Pathology20122510331039. (doi:10.1038/modpathol.2012.53).

  • 94

    HeaphyCMde WildeRFJiaoYKleinAPEdilBHShiCBettegowdaCRodriguezFJEberhartCGHebbarS. Altered telomeres in tumors with ATRX and DAXX mutations. Science2011333425. (doi:10.1126/science.1207313).

  • 95

    LovejoyCALiWReisenweberSThongthipSBrunoJde LangeTDeSPetriniJHSungPAJasinM. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genetics20128e1002772. (doi:10.1371/journal.pgen.1002772).

  • 96

    PipinikasCDibraHKarpathakisAFeberANovelliMOukrifDFusaiGValenteRCaplinMMeyerT. Epigenetic dysregulation and poorer outcome in DAXX deficient PNETs. Endocrine-Related Cancer201522L13L18. (doi:10.1530/ERC-15-0108).

  • 97

    HuWFengZModicaIKlimstraDSSongLAllenPJBrennanMFLevineAJTangLH. Gene amplifications in well-differentiated pancreatic neuroendocrine tumors inactivate the p53 pathway. Genes & Cancer20101360368. (doi:10.1177/1947601910371979).

  • 98

    CaoYGaoZLiLJiangXShanACaiJPengYLiYJiangXHuangX. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nature Communications201342810. (doi:10.1038/ncomms3810).

  • 99

    LichtenauerUDDi DalmaziGSlaterEPWielandTKuebartASchmittfullASchwarzmayrTDienerSWieseDThaslerWE. Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas. Journal of Clinical Endocrinology and Metabolism2015100E776E782. (doi:10.1210/jc.2015-1100).

  • 100

    CromerMKChoiMNelson-WilliamsCFonsecaALKunstmanJWKorahRMOvertonJDManeSKenneyBMalchoffCD. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. PNAS201511240624067. (doi:10.1073/pnas.1503696112).

  • 101

    JonkersYMClaessenSMPerrenASchmittAMHoflandLJde HerderWde KrijgerRRVerhofstadAAHermusARKummerJA. DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients. Endocrine-Related Cancer200714769779. (doi:10.1677/ERC-07-0111).

  • 102

    DebelenkoLVEmmert-BuckMRZhuangZEpshteynEMoskalukCAJensenRTLiottaLALubenskyIA. The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology1997113773781. (doi:10.1016/S0016-5085(97)70171-9).

  • 103

    CaiJLiLYeLJiangXShenLGaoZFangWHuangFSuTZhouY. Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis. Endocrine-Related Cancer2015222333. (doi:10.1530/ERC-14-0225).

  • 104

    AgrawalNJiaoYSausenMLearyRBettegowdaCRobertsNJBhanSHoASKhanZBishopJ. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. Journal of Clinical Endocrinology and Metabolism201398E364E369. (doi:10.1210/jc.2012-2703).

  • 105

    MouraMMCavacoBMPintoAELeiteV. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism201196E863E868. (doi:10.1210/jc.2010-1921).

  • 106

    CiampiRMianCFugazzolaLCosciBRomeiCBarolloSCirelloVBotticiVMarconciniGRosaPM. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid2013235057. (doi:10.1089/thy.2012.0207).

  • 107

    JiJHOhYLHongMYunJWLeeHWKimDJiYKimDHParkWYShinHT. Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer. PLoS Genetics201511e1005467. (doi:10.1371/journal.pgen.1005467).

  • 108

    ShawATKimDWMehraRTanDSFelipEChowLQCamidgeDRVansteenkisteJSharmaSDe PasT. Ceritinib in ALK-rearranged non-small-cell lung cancer. New England Journal of Medicine201437011891197. (doi:10.1056/NEJMoa1311107).

  • 109

    SchlisioSKenchappaRSVredeveldLCGeorgeREStewartRGreulichHShahriariKNguyenNVPignyPDahiaPL. The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes and Development200822884893. (doi:10.1101/gad.1648608).

  • 110

    WelanderJAndreassonAJuhlinCCWisemanRWBackdahlMHoogALarssonCGimmOSoderkvistP. Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism201499E1352E1360. (doi:10.1210/jc.2013-4375).

  • 111

    GaalJBurnichonNKorpershoekERoncelinIBertheratJPlouinPFde KrijgerRRGimenez-RoqueploAPDinjensWN. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism20109512741278. (doi:10.1210/jc.2009-2170).

  • 112

    WadtKChoiJChungJYKiilgaardJHeegaardSDrzewieckiKTTrentJMHewittSMHaywardNKGerdesAM. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell & Melanoma Research201225815818. (doi:10.1111/pcmr.12006).

  • 113

    LadroueCCarcenacRLeporrierMGadSLe HelloCGalateau-SalleFFeunteunJPouyssegurJRichardSGardieB. PHD2 mutation and congenital erythrocytosis with paraganglioma. New England Journal of Medicine200835926852692. (doi:10.1056/NEJMoa0806277).

  • 114

    YangCZhuangZFliednerSMShankavaramUSunMGBullovaPZhuRElkahlounAGKourlasPJMerinoM. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. Journal of Molecular Medicine20159393104. (doi:10.1007/s00109-014-1205-7).

  • 115

    CronaJDelgado VerdugoAMaharjanRStalbergPGranbergDHellmanPBjorklundP. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. Journal of Clinical Endocrinology and Metabolism201398E1266E1271. (doi:10.1210/jc.2012-4257).

  • 116

    OudijkLde KrijgerRRRapaIBeuschleinFde CubasAADei TosAPDinjensWNKorpershoekEMancikovaVMannelliM. H-RAS mutations are restricted to sporadic pheochromocytomas lacking specific clinical or pathological features: data from a multi-institutional series. Journal of Clinical Endocrinology and Metabolism201499E1376E1380. (doi:10.1210/jc.2013-3879).

  • 117

    FishbeinLKhareSWubbenhorstBDeSlooverDD'AndreaKMerrillSChoNWGreenbergRAElseTMontoneK. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nature Communications201566140. (doi:10.1038/ncomms7140).

  • 118

    PapathomasTOudijkLZwarthoffECPostEDuijkersFAvan NoeselMHoflandLPollardPJMaherERRestucciaDF. TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. Endocrine-Related Cancer201421653661. (doi:10.1530/ERC-13-0429).

  • 119

    LiuTBrownTCJuhlinCCAndreassonAWangNBackdahlMHealyJMPrasadMLKorahRCarlingT. The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors. Endocrine-Related Cancer201421427434. (doi:10.1530/ERC-14-0016).

  • 120

    JuhlinCCStenmanAHaglundFClarkVEBrownTCBaranoskiJBilguvarKGohGWelanderJSvahnF. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes Chromosomes & Cancer201554542554. (doi:10.1002/gcc.22267).

  • 121

    Castro-VegaLJLetouzeEBurnichonNBuffetADisderotPHKhalifaELoriotCElarouciNMorinAMenaraM. Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nature Communications201566044. (doi:10.1038/ncomms7044).

  • 122

    FlynnABennDClifton-BlighRRobinsonBTrainerAHJamesPHoggAWaldeckKGeorgeJLiJ. The genomic landscape of phaeochromocytoma. Journal of Pathology20152367889. (doi:10.1002/path.4503).

  • 123

    DahiaPLRossKNWrightMEHayashidaCYSantagataSBarontiniMKungALSansoGPowersJFTischlerAS. A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genetics200517280. (doi:10.1371/journal.pgen.0010008).

  • 124

    BurnichonNVescovoLAmarLLibeRde ReyniesAVenisseAJouannoELaurendeauIParfaitBBertheratJ. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Human Molecular Genetics20112039743985. (doi:10.1093/hmg/ddr324).

  • 125

    QinYDengYRickettsCJSrikantanSWangEMaherERDahiaPL. The tumor susceptibility gene TMEM127 is mutated in renal cell carcinomas and modulates endolysosomal function. Human Molecular Genetics20142324282439. (doi:10.1093/hmg/ddt638).

  • 126

    Travis WD Müller-Hermelink HK Harris CC Brambilla E. Pathology and Genetics. In WHO Classification of Tumours. Lyon: IARC Press 2004

  • 127

    SachithanandanNHarleRABurgessJR. Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer2005103509515. (doi:10.1002/cncr.20825).

  • 128

    Fernandez-CuestaLPeiferMLuXSunROzreticLSeidelDZanderTLeendersFGeorgeJMullerC. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nature Communications201453518. (doi:10.1038/ncomms4518).

  • 129

    DebelenkoLVBrambillaEAgarwalSKSwalwellJIKesterMBLubenskyIAZhuangZGuruSCManickamPOlufemiSE. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Human Molecular Genetics1997622852290. (doi:10.1093/hmg/6.13.2285).

  • 130

    RapaIVottaAFeliceBRighiLGiorcelliJScarpaASpeelEJScagliottiGVPapottiMVolanteM. Identification of microRNAs differentially expressed in lung carcinoid subtypes and progression. Neuroendocrinology2015101246255. (doi:10.1159/000381454).

  • 131

    StrobelPZettlAShiloKChuangWYNicholsonAGMatsunoYGalALaengRHEngelPCapellaC. Tumor genetics and survival of thymic neuroendocrine neoplasms: a multi-institutional clinicopathologic study. Genes Chromosomes & Cancer201453738749. (doi:10.1002/gcc.22183).

  • 132

    FujiiTKawaiTSaitoKHishimaTHayashiYImuraJHironakaMHosoyaYKoikeMFukayamaM. MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation. Pathology International199949968973. (doi:10.1046/j.1440-1827.1999.00971.x).

  • 133

    CunninghamJLDiaz de StahlTSjoblomTWestinGDumanskiJPJansonET. Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes Chromosomes & Cancer2011508294. (doi:10.1002/gcc.20834).

  • 134

    NeklasonDVanDersliceJCurtinKCannon-AlbrightLA. Evidence for a heritable contribution to neuroendocrine tumors of the small intestine. Endocrine-Related Cancer20162393100. (doi:10.1530/ERC-15-0442).

  • 135

    SeiYZhaoXForbesJSzymczakSLiQTrivediAVoellingerMJoyGFengJWhatleyM. A hereditary form of small intestinal carcinoid associated with a germline mutation in inositol polyphosphate multikinase. Gastroenterology20151496778. (doi:10.1053/j.gastro.2015.04.008).

  • 136

    FrancisJMKiezunARamosAHSerraSPedamalluCSQianZRBanckMSKanwarRKulkarniAAKarpathakisA. Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nature Genetics20134514831486. (doi:10.1038/ng.2821).

  • 137

    BanckMSKanwarRKulkarniAABooraGKMetgeFKippBRZhangLThorlandECMinnKTTentuR. The genomic landscape of small intestine neuroendocrine tumors. Journal of Clinical Investigation201312325022508. (doi:10.1172/JCI67963).

  • 138

    CronaJGustavssonTNorlenOEdfeldtKAkerstromTWestinGHellmanPBjorklundPStalbergP. Somatic mutations and genetic heterogeneity at the CDKN1B locus in small intestinal neuroendocrine tumors. Annals of Surgical Oncology201522 (Suppl 3) 14281435. (doi:10.1245/s10434-014-4351-9).

  • 139

    KulkeMHFreedEChiangDYPhilipsJZahriehDGlickmanJNShivdasaniRA. High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes & Cancer200847591603. (doi:10.1002/gcc.20561).

  • 140

    KarpathakisADibraHPipinikasCFeberAMorrisTFrancisJMOukrifDMandairDPericleousMMohmaduveshM. Prognostic impact of novel molecular subtypes of small intestinal neuroendocrine tumour. Clinical Cancer Research201622250258. (doi:10.1158/1078-0432.CCR-15-0373).

  • 141

    VerdugoADCronaJStarkerLStalbergPAkerstromGWestinGHellmanPBjorklundP. Global DNA methylation patterns through an array-based approach in small intestinal neuroendocrine tumors. Endocrine-Related Cancer201421L5L7. (doi:10.1530/ERC-13-0481).

  • 142

    EdfeldtKBjorklundPAkerstromGWestinGHellmanPStalbergP. Different gene expression profiles in metastasizing midgut carcinoid tumors. Endocrine-Related Cancer201118479489. (doi:10.1530/ERC-10-0256).

  • 143

    HessmanOSkogseidBWestinGAkerstromG. Multiple allelic deletions and intratumoral genetic heterogeneity in men1 pancreatic tumors. Journal of Clinical Endocrinology and Metabolism20018613551361. (doi:10.1210/jcem.86.3.7332).

  • 144

    KatonaTMJonesTDWangMAbdul-KarimFWCummingsOWChengL. Molecular evidence for independent origin of multifocal neuroendocrine tumors of the enteropancreatic axis. Cancer Research20066649364942. (doi:10.1158/0008-5472.CAN-05-4184).

  • 145

    GuoZLiQWilanderEPontenJ. Clonality analysis of multifocal carcinoid tumours of the small intestine by X-chromosome inactivation analysis. Journal of Pathology20001907679. (doi:10.1002/(SICI)1096-9896(200001)190:1<76::AID-PATH499>3.0.CO;2-1).

  • 146

    GoebelSUVortmeyerAOZhuangZSerranoJJensenRTLubenskyIA. Identical clonality of sporadic gastrinomas at multiple sites. Cancer Research2000606063.

  • 147

    BaylinSBGannDSHsuSH. Clonal origin of inherited medullary thyroid carcinoma and pheochromocytoma. Science1976193321323. (doi:10.1126/science.935869).

  • 148

    FriedmanESakaguchiKBaleAEFalchettiAStreetenEZimeringMBWeinsteinLSMcBrideWONakamuraYBrandiML. Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. New England Journal of Medicine1989321213218. (doi:10.1056/NEJM198907273210402).

  • 149

    StrosbergJRWeberJMFeldmanMCoppolaDMeredithKKvolsLK. Prognostic validity of the American Joint Committee on Cancer staging classification for midgut neuroendocrine tumors. Journal of Clinical Oncology201331420425. (doi:10.1200/JCO.2012.44.5924).

  • 150

    KorpershoekEStobbeCKvan NederveenFHde KrijgerRRDinjensWN. Intra-tumoral molecular heterogeneity in benign and malignant pheochromocytomas and extra-adrenal sympathetic paragangliomas. Endocrine-Related Cancer201017653662. (doi:10.1677/ERC-10-0072).

  • 151

    KorpershoekEPetriBJPostEvan EijckCHOldenburgRABeltEJde HerderWWde KrijgerRRDinjensWN. Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome. Neoplasia201416868873. (doi:10.1016/j.neo.2014.09.002).

  • 152

    CronaJBackmanSMaharjanRMayrhoferMStalbergPIsaksonAHellmanPBjorklundP. Spatio-temporal heterogeneity characterizes the genetic landscape of pheochromocytoma and defines early events in tumourigenesis. Clinical Cancer Research20152144514460. (doi:10.1158/1078-0432.CCR-14-2854).

  • 153

    PaezJGJannePALeeJCTracySGreulichHGabrielSHermanPKayeFJLindemanNBoggonTJ. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science200430414971500. (doi:10.1126/science.1099314).

  • 154

    KarapetisCSKhambata-FordSJonkerDJO'CallaghanCJTuDTebbuttNCSimesRJChalchalHShapiroJDRobitailleS. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine200835917571765. (doi:10.1056/NEJMoa0804385).

  • 155

    WagleNGrabinerBCVan AllenEMHodisEJacobusSSupkoJGStewartMChoueiriTKGandhiLClearyJM. Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discovery20144546553. (doi:10.1158/2159-8290.CD-13-0353).

  • 156

    WagleNGrabinerBCVan AllenEMAmin-MansourATaylor-WeinerARosenbergMGrayNBarlettaJAGuoYSwansonSJ. Response and acquired resistance to everolimus in anaplastic thyroid cancer. New England Journal of Medicine201437114261433. (doi:10.1056/NEJMoa1403352).

  • 157

    FrancoisRAMaengKNawabAKayeFJHochwaldSNZajac-KayeM. Targeting focal adhesion kinase and resistance to mTOR inhibition in pancreatic neuroendocrine tumors. Journal of the National Cancer Institute2015107doi:10.1093/jnci/djv123).

  • 158

    JiangXCaoYLiFSuYLiYPengYChengYZhangCWangWNingG. Targeting β-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours. Nature Communications201455809. (doi:10.1038/ncomms6809).

  • 159

    SnyderAMakarovVMerghoubTYuanJZaretskyJMDesrichardAWalshLAPostowMAWongPHoTS. Genetic basis for clinical response to CTLA-4 blockade in melanoma. New England Journal of Medicine201437121892199. (doi:10.1056/NEJMoa1406498).

  • 160

    BrownSDWarrenRLGibbEAMartinSDSpinelliJJNelsonBHHoltRA. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Research201424743750. (doi:10.1101/gr.165985.113).

  • 161

    KreiterSVormehrMvan de RoemerNDikenMLowerMDiekmannJBoegelSSchrorsBVascottoFCastleJC. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature2015520692696. (doi:10.1038/nature14426).

  • 162

    FlynnRLCoxKEJeitanyMWakimotoHBryllARGanemNJBersaniFPinedaJRSuvaMLBenesCH. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science2015347273277. (doi:10.1126/science.1257216).

  • 163

    VandammeTPeetersMDoganFPauwelsPVan AsscheEBeyensMMortierGVandeweyerGde HerderWVan CampG. Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. Journal of Molecular Endocrinology201554137147. (doi:10.1530/JME-14-0304).

  • 164

    VandammeTBeyensMPeetersMVan CampGde BeeckKO. Next generation exome sequencing of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1 reveals different lineages. Cancer Genetics2015208523. (doi:10.1016/j.cancergen.2015.07.003).

  • 165

    CronaJDelgado VerdugoAGranbergDWelinSStålbergPHellmanPBjörklundP. Next generation sequencing in genetic screening of pheochromocytoma and paraganglioma. Endocrine Connections20132104111. (doi:10.1530/EC-13-0009).

  • 166

    CronaJLjungstromVWelinSWalzMKHellmanPBjorklundP. Bioinformatic challenges in clinical diagnostic application of targeted next generation sequencing: experience from pheochromocytoma. PLoS ONE201510e0133210. (doi:10.1371/journal.pone.0133210).

  • 167

    SimboloMMianCBarolloSFassanMMafficiniANevesDScardoniMPennelliGRuggeMPelizzoMR. High-throughput mutation profiling improves diagnostic stratification of sporadic medullary thyroid carcinomas. Virchows Archiv20144657378. (doi:10.1007/s00428-014-1589-3).

  • 168

    KhanMSKirkwoodAATsiganiTLoweHGoldsteinRHartleyJACaplinMEMeyerT. Early changes in circulating tumor cells are associated with response and survival following treatment of metastatic neuroendocrine neoplasms. Clinical Cancer Research2016227985. (doi:10.1158/1078-0432.CCR-15-1008).

  • 169

    KhanMSKirkwoodATsiganiTGarcia-HernandezJHartleyJACaplinMEMeyerT. Circulating tumor cells as prognostic markers in neuroendocrine tumors. Journal of Clinical Oncology201331365372. (doi:10.1200/JCO.2012.44.2905).

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1323 1323 254
PDF Downloads 477 477 90

Altmetrics

Figures

  • View in gallery

    Overview of genes with recurrent mutations in NETs and their distribution accordingly to anatomical location.

  • View in gallery

    Overview of mutational burden in NETs merged from raw data in (80, 85, 86, 87, 98, 99, 100, 104, 117, 120, 121, 122, 128, 136, 137). Each dot represents a unique tumor, and the line shows the median number of mutations of each category. PT, parathyroid.

  • View in gallery

    Simplified overview of genes and pathways involved in NET tumorigenesis.

  • View in gallery

    Theory of evolution, with relevant driver genes, in NET tumorigenesis. The 15 genes involved in pheochromocytoma and PGL tumorigenesis are: SDHx, SDHAF2, MDH2, VHL, EPAS1, NF1, RET, HRAS, TMEM127, MAX, KIF1B and KMT2D.

References

1

ModlinIMObergKChungDCJensenRTde HerderWWThakkerRVCaplinMDelle FaveGKaltsasGAKrenningEP. Gastroenteropancreatic neuroendocrine tumours. Lancet. Oncology200896172. (doi:10.1016/S1470-2045(07)70410-2).

2

EkebladSSkogseidBDunderKObergKErikssonB. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clinical Cancer Research20081477987803. (doi:10.1158/1078-0432.CCR-08-0734).

3

NorlenOStalbergPObergKErikssonJHedbergJHessmanOJansonETHellmanPAkerstromG. Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center. World Journal of Surgery20123614191431. (doi:10.1007/s00268-011-1296-z).

4

GrandeECapdevilaJBarriusoJAnton-AparicioLCastellanoD. Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist?Cancer Metastasis Reviews2012314753. (doi:10.1007/s10555-011-9328-6).

5

HalletJLawCHCukierMSaskinRLiuNSinghS. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer2015121589597. (doi:10.1002/cncr.29099).

6

YaoJCHassanMPhanADagohoyCLearyCMaresJEAbdallaEKFlemingJBVautheyJNRashidA. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. Journal of Clinical Oncology20082630633072. (doi:10.1200/JCO.2007.15.4377).

7

WermerP. Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine195416363371. (doi:10.1016/0002-9343(54)90353-8).

8

BrandiMLGagelRFAngeliABilezikianJPBeck-PeccozPBordiCConte-DevolxBFalchettiAGheriRGLibroiaA. Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism20018656585671. (doi:10.1210/jcem.86.12.8070).

9

LarssonCSkogseidBObergKNakamuraYNordenskjoldM. Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. Nature19883328587. (doi:10.1038/332085a0).

10

ChandrasekharappaSCGuruSCManickamPOlufemiSECollinsFSEmmert-BuckMRDebelenkoLVZhuangZLubenskyIALiottaLA. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science1997276404407. (doi:10.1126/science.276.5311.404).

11

ThakkerRV. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology2014386215. (doi:10.1016/j.mce.2013.08.002).

12

PellegataNSQuintanilla-MartinezLSiggelkowHSamsonEBinkKHoflerHFendFGrawJAtkinsonMJ. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. PNAS20061031555815563. (doi:10.1073/pnas.0603877103).

13

LonguiniVCLourencoDMJrSekiyaTMeirellesOGoncalvesTDCoutinhoFLFranciscoGOsakiLHChammasRAlvesVA. Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations. European Journal of Endocrinology/European Federation of Endocrine Societies2014171335342. (doi:10.1530/EJE-14-0130).

14

AnlaufMPerrenAHenoppTRudolfTGarbrechtNSchmittARaffelAGimmOWeiheEKnoefelWT. Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions. Gut200756637644. (doi:10.1136/gut.2006.108910).

15

AgarwalSK. Multiple endocrine neoplasia type 1. Frontiers of Hormone Research201341115. (doi:10.1159/000345666).

16

WellsSAJrPaciniFRobinsonBGSantoroM. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. Journal of Clinical Endocrinology and Metabolism20139831493164. (doi:10.1210/jc.2013-1204).

17

SteinerALGoodmanADPowersSR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia, type 2. Medicine196847371409. (doi:10.1097/00005792-196809000-00001).

18

MorrisonPJNevinNC. Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann–Froboese syndrome). Journal of Medical Genetics199633779782. (doi:10.1136/jmg.33.9.779).

19

Donis-KellerHDouSChiDCarlsonKMToshimaKLairmoreTCHoweJRMoleyJFGoodfellowPWellsSAJr. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics19932851856. (doi:10.1093/hmg/2.7.851).

20

MulliganLMKwokJBHealeyCSElsdonMJEngCGardnerELoveDRMoleSEMooreJKPapiL. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature1993363458460. (doi:10.1038/363458a0).

21

SippleJ. The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine196131163166. (doi:10.1016/0002-9343(61)90234-0).

22

WellsSAJrSantoroM. Targeting the RET pathway in thyroid cancer. Clinical Cancer Research20091571197123. (doi:10.1158/1078-0432.CCR-08-2742).

23

PonderBA. The phenotypes associated with ret mutations in the multiple endocrine neoplasia type 2 syndrome. Cancer Research1999591736s1741s; discussion 1742s.

24

MukherjeeSZakalikD. RET codon 804 mutations in multiple endocrine neoplasia 2: genotype–phenotype correlations and implications in clinical management. Clinical Genetics201179116. (doi:10.1111/j.1399-0004.2010.01453.x).

25

KloosRTEngCEvansDBFrancisGLGagelRFGharibHMoleyJFPaciniFRingelMDSchlumbergerM. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid200919565612. (doi:10.1089/thy.2008.0403).

26

ChenHSippelRSO'DorisioMSVinikAILloydRVPacakK. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas201039775783. (doi:10.1097/MPA.0b013e3181ebb4f0).

27

FarndonJRLeightGSDilleyWGBaylinSBSmallridgeRCHarrisonTSWellsSAJr. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. British Journal of Surgery198673278281. (doi:10.1002/bjs.1800730411).

28

Crowe F Schull W Neel J. A Clinical Pathologicala and Genetic Study of Multiple Neurofibromatosis. Springfield IL: Charles C Thomas 1956

29

McGaughranJMHarrisDIDonnaiDTeareDMacLeodRWesterbeekRKingstonHSuperMHarrisREvansDG. A clinical study of type 1 neurofibromatosis in north west England. Journal of Medical Genetics199936197203.

30

GriffithsDFWilliamsGTWilliamsED. Duodenal carcinoid tumours, phaeochromocytoma and neurofibromatosis: islet cell tumour, phaeochromocytoma and the von Hippel–Lindau complex: two distinctive neuroendocrine syndromes. Quarterly Journal of Medicine198764769782.

31

MartinGAViskochilDBollagGMcCabePCCrosierWJHaubruckHConroyLClarkRO'ConnellPCawthonRM. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell199063843849. (doi:10.1016/0092-8674(90)90150-D).

32

WallaceMRMarchukDAAndersenLBLetcherROdehHMSaulinoAMFountainJWBreretonANicholsonJMitchellAL. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science1990249181186. (doi:10.1126/science.2134734).

33

MaherERIseliusLYatesJRLittlerMBenjaminCHarrisRSampsonJWilliamsAFerguson-SmithMAMortonN. Von Hippel–Lindau disease: a genetic study. Journal of Medical Genetics199128443447. (doi:10.1136/jmg.28.7.443).

34

Nordstrom-O'BrienMvan der LuijtRBvan RooijenEvan den OuwelandAMMajoor-KrakauerDFLolkemaMPvan BrusselAVoestEEGilesRH. Genetic analysis of von Hippel–Lindau disease. Human Mutation201031521537. (doi:10.1002/humu.21219).

35

ChenFKishidaTYaoMHustadTGlavacDDeanMGnarraJROrcuttMLDuhFMGlennG. Germline mutations in the von Hippel–Lindau disease tumor suppressor gene: correlations with phenotype. Human Mutation199556675. (doi:10.1002/humu.1380050109).

36

BurnichonNBriereJJLibeRVescovoLRiviereJTissierFJouannoEJeunemaitreXBenitPTzagoloffA. SDHA is a tumor suppressor gene causing paraganglioma. Human Molecular Genetics20101930113020. (doi:10.1093/hmg/ddq206).

37

AstutiDLatifFDallolADahiaPLDouglasFGeorgeESkoldbergFHusebyeESEngCMaherER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics2001694954. (doi:10.1086/321282).

38

NiemannSMullerU. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nature Genetics200026268270. (doi:10.1038/81551).

39

BaysalBEFerrellREWillett-BrozickJELawrenceECMyssiorekDBoschAvan der MeyATaschnerPERubinsteinWSMyersEN. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science2000287848851. (doi:10.1126/science.287.5454.848).

40

HaoHXKhalimonchukOSchradersMDephoureNBayleyJPKunstHDevileePCremersCWSchiffmanJDBentzBG. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science200932511391142. (doi:10.1126/science.1175689).

41

LetouzeEMartinelliCLoriotCBurnichonNAbermilNOttolenghiCJaninMMenaraMNguyenATBenitP. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell2013210018300189. (doi:10.1016/j.ccr.2013.04.018).

42

LatifFToryKGnarraJYaoMDuhFMOrcuttMLStackhouseTKuzminIModiWGeilL. Identification of the von Hippel–Lindau disease tumor suppressor gene. Science199326013171320. (doi:10.1126/science.8493574).

43

ZhuangZYangCLorenzoFMerinoMFojoTKebebewEPopovicVStratakisCAPrchalJTPacakK. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. New England Journal of Medicine2012367922930. (doi:10.1056/NEJMoa1205119).

44

QinYYaoLKingEEBuddavarapuKLenciREChocronESLechleiterJDSassMAroninNSchiaviF. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nature Genetics201042229233. (doi:10.1038/ng.533).

45

Comino-MendezIGracia-AznarezFJSchiaviFLandaILeandro-GarciaLJLetonRHonradoERamos-MedinaRCaroniaDPitaG. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nature Genetics201143663667. (doi:10.1038/ng.861).

46

RichterSPeitzschMRapizziELendersJWQinNde CubasAASchiaviFRaoJUBeuschleinFQuinklerM. Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas/paragangliomas due to succinate dehydrogenase deficiency. Journal of Clinical Endocrinology and Metabolism20149939033911. (doi:10.1210/jc.2014-2151).

47

WelanderJSoderkvistPGimmO. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer201118R253R276. (doi:10.1530/ERC-11-0170).

48

van der MeyAGMaaswinkel-MooyPDCornelisseCJSchmidtPHvan de KampJJ. Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory. Lancet1989212911294. (doi:10.1016/S0140-6736(89)91908-9).

49

BurnichonNRohmerVAmarLHermanPLeboulleuxSDarrouzetVNiccoliPGaillardDChabrierGChabolleF. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. Journal of Clinical Endocrinology and Metabolism20099428172827. (doi:10.1210/jc.2008-2504).

50

NeumannHPPawluCPeczkowskaMBauschBMcWhinneySRMuresanMBuchtaMFrankeGKlischJBleyTA. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association2004292943951. (doi:10.1001/jama.292.8.943).

51

van HulsteijnLTDekkersOMHesFJSmitJWCorssmitEP. Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. Journal of Medical Genetics20122525. (doi:10.1136/jmedgenet-2012-101192).

52

van BaarsFCremersCvan den BroekPGeertsSVeldmanJ. Genetic aspects of nonchromaffin paraganglioma. Human Genetics198260305309. (doi:10.1007/BF00569208).

53

BayleyJPKunstHPCasconASampietroMLGaalJKorpershoekEHinojar-GutierrezATimmersHJHoefslootLHHermsenMA. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet. Oncology201011366372. (doi:10.1016/S1470-2045(10)70007-3).

54

CaseyRGarrahyATuthillAO'HalloranDJoyceCCaseyMBO'SheaPBellM. Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation. Journal of Clinical Endocrinology and Metabolism201499E1392E1396. (doi:10.1210/jc.2013-4536).

55

NiemannSSteinbergerDMullerU. PGL3, a third, not maternally imprinted locus in autosomal dominant paraganglioma. Neurogenetics19992167170. (doi:10.1007/s100480050078).

56

HensenEFvan DuinenNJansenJCCorssmitEPTopsCMRomijnJAVriendsAHvan der MeyAGCornelisseCJDevileeP. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clinical Genetics201281284288. (doi:10.1111/j.1399-0004.2011.01653.x).

57

MannelliMErcolinoTGiacheVSimiLCiramiCParentiG. Genetic screening for pheochromocytoma: should SDHC gene analysis be included?Journal of Medical Genetics200744586587. (doi:10.1136/jmg.2007.051045).

58

Gimenez-RoqueploAPFavierJRustinPRieublandCCrespinMNauVKhau Van KienPCorvolPPlouinPFJeunemaitreX. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Research20036356155621.

59

BogdasarianRLotzP. Multiple simultaneous paragangliomas of the head and neck in association with multiple retroperitoneal pheochromocytomas. Otolaryngology – Head and Neck Surgery197987648652.

60

KorpershoekEFavierJGaalJBurnichonNvan GesselBOudijkLBadoualCGadessaudNVenisseABayleyJP. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. Journal of Clinical Endocrinology and Metabolism201196E1472E1476. (doi:10.1210/jc.2011-1043).

61

PantaleoMAAstolfiAIndioVMooreRThiessenNHeinrichMCGnocchiCSantiniDCatenaFFormicaS. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. Journal of the National Cancer Institute2011103983987. (doi:10.1093/jnci/djr130).

62

YaoLSchiaviFCasconAQinYInglada-PerezLKingEEToledoRAErcolinoTRapizziERickettsCJ. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. Journal of the American Medical Association201030426112619. (doi:10.1001/jama.2010.1830).

63

AbermilNGuillaud-BatailleMBurnichonNVenisseAManivetPGuignatLDruiDChupinMJosseaumeCAffresH. TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. Journal of Clinical Endocrinology and Metabolism201297E805E809. (doi:10.1210/jc.2011-3360).

64

ToledoSPLourencoDMJrSekiyaTLuconAMBaenaMECastroCCBortolottoLAZerbiniMCSiqueiraSAToledoRA. Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation. Journal of Clinical Endocrinology and Metabolism2015100E308E318. (doi:10.1210/jc.2014-2473).

65

BurnichonNCasconASchiaviFPaes MoralesNComino-MendezIAbermilNInglada-PerezLde CubasAAAmarLBarontiniMB. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research20121828282837. (doi:10.1158/1078-0432.CCR-12-0160).

66

SmitDLMensenkampARBadeloeSBreuningMHSimonMEvan SpaendonckKYAalfsCMPostJGShanleySKrapelsIP. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clinical Genetics2011794959. (doi:10.1111/j.1399-0004.2010.01486.x).

67

ClarkGRSciacovelliMGaudeEWalshDMKirbyGSimpsonMATrembathRCBergJNWoodwardERKinningE. Germline FH mutations presenting with pheochromocytoma. Journal of Clinical Endocrinology and Metabolism201499E2046E2050. (doi:10.1210/jc.2014-1659).

68

Castro-VegaLJBuffetADe CubasAACasconAMenaraMKhalifaEAmarLAzrielSBourdeauIChabreO. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Human Molecular Genetics20142324402446. (doi:10.1093/hmg/ddt639).

69

CasconAComino-MendezICurras-FreixesMde CubasAAContrerasLRichterSPeitzschMMancikovaVInglada-PerezLPerez-BarriosA. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. Journal of the National Cancer Institute2015107Article ID: djv053doi:10.1093/jnci/djv053).

70

LorenzoFRYangCNg Tang FuiMVankayalapatiHZhuangZHuynhTGrossmannMPacakKPrchalJT. A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. Journal of Molecular Medicine201291507512. (doi:10.1007/s00109-012-0967-z).

71

Comino-MendezIde CubasAABernalCAlvarez-EscolaCSanchez-MaloCRamirez-TortosaCLPedrinaciSRapizziEErcolinoTBerniniG. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Human Molecular Genetics20132221692176. (doi:10.1093/hmg/ddt069).

72

PacakKJochmanovaIProdanovTYangCMerinoMJFojoTPrchalJTTischlerASLechanRMZhuangZ. New syndrome of paraganglioma and somatostatinoma associated with polycythemia. Journal of Clinical Oncology20133116901698. (doi:10.1200/JCO.2012.47.1912).

73

PacakKChewEYPappoASYangCLorenzoFRWilsonMWAronowMBYoungJAPopovicVZhuangZ. Ocular manifestations of hypoxia-inducible factor-2α paraganglioma-somatostatinoma-polycythemia syndrome. Ophthalmology201412122912293. (doi:10.1016/j.ophtha.2014.06.019).

74

van SlegtenhorstMde HoogtRHermansCNellistMJanssenBVerhoefSLindhoutDvan den OuwelandAHalleyDYoungJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science1997277805808. (doi:10.1126/science.277.5327.805).

75

Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell19937513051315. (doi:10.1016/0092-8674(93)90618-Z).

76

OsborneJPFryerAWebbD. Epidemiology of tuberous sclerosis. Annals of the New York Academy of Sciences1991615125127. (doi:10.1111/j.1749-6632.1991.tb37754.x).

77

CuratoloPBombardieriRJozwiakS. Tuberous sclerosis. Lancet2008372657668. (doi:10.1016/S0140-6736(08)61279-9).

78

DworakowskaDGrossmanAB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocrine-Related Cancer2009164558. (doi:10.1677/ERC-08-0142).

79

InokiKLiYZhuTWuJGuanKL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology20024648657. (doi:10.1038/ncb839).

80

JiaoYShiCEdilBHde WildeRFKlimstraDSMaitraASchulickRDTangLHWolfgangCLChotiMA. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science201133111991203. (doi:10.1126/science.1200609).

81

CarptenJDRobbinsCMVillablancaAForsbergLPresciuttiniSBailey-WilsonJSimondsWFGillandersEMKennedyAMChenJD. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature Genetics200232676680. (doi:10.1038/ng1048).

82

JacksonCENorumRABoydSBTalposGBWilsonSDTaggartRTMalletteLE. Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome. Surgery199010810061012; discussion 1012-1003.

83

PollakMRBrownEMChouYHHebertSCMarxSJSteinmannBLeviTSeidmanCESeidmanJG. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell19937512971303. (doi:10.1016/0092-8674(93)90617-Y).

84

LemmensIVan de VenWJKasKZhangCXGiraudSWautotVBuissonNDe WitteKSalandreJLenoirG. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Human Molecular Genetics1997611771183. (doi:10.1093/hmg/6.7.1177).

85

CromerMKStarkerLFChoiMUdelsmanRNelson-WilliamsCLiftonRPCarlingT. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. Journal of Clinical Endocrinology and Metabolism201297E1774E1781. (doi:10.1210/jc.2012-1743).

86

NeweyPJNesbitMARimmerAJAttarMHeadRTChristiePTGorvinCMStechmanMGregoryLMihaiR. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. Journal of Clinical Endocrinology and Metabolism201297E1995E2005. (doi:10.1210/jc.2012-2303).

87

YuWMcPhersonJRStevensonMvanEijkRHengHLNeweyPGanARuanoDHuangDPoonSL. Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. Journal of Clinical Endocrinology and Metabolism2015100E360E364. (doi:10.1210/jc.2014-3238).

88

BurnsMBTemizNAHarrisRS. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics201345977983. (doi:10.1038/ng.2701).

89

PerrenAKomminothPSaremaslaniPMatterCFeurerSLeesJAHeitzPUEngC. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. American Journal of Pathology200015710971103. (doi:10.1016/S0002-9440(10)64624-X).

90

ZhuangZVortmeyerAOPackSHuangSPhamTAWangCParkWSAgarwalSKDebelenkoLVKesterM. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Research19975746824686.

91

SadanandamAWullschlegerSLyssiotisCAGrotzingerCBarbiSBersaniSKornerJWafyIMafficiniALawlorRT. A cross-species analysis in pancreatic neuroendocrine tumors reveals molecular subtypes with distinctive clinical, metastatic, developmental, and metabolic characteristics. Cancer Discovery2015512961313. (doi:10.1158/2159-8290.CD-15-0068).

92

MarinoniIKurrerASVassellaEDettmerMRudolphTBanzVHungerFPasquinelliSSpeelEJPerrenA. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology2014146453460.e455. (doi:10.1053/j.gastro.2013.10.020).

93

de WildeRFHeaphyCMMaitraAMeekerAKEdilBHWolfgangCLEllisonTASchulickRDMolenaarIQValkGD. Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Modern Pathology20122510331039. (doi:10.1038/modpathol.2012.53).

94

HeaphyCMde WildeRFJiaoYKleinAPEdilBHShiCBettegowdaCRodriguezFJEberhartCGHebbarS. Altered telomeres in tumors with ATRX and DAXX mutations. Science2011333425. (doi:10.1126/science.1207313).

95

LovejoyCALiWReisenweberSThongthipSBrunoJde LangeTDeSPetriniJHSungPAJasinM. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genetics20128e1002772. (doi:10.1371/journal.pgen.1002772).

96

PipinikasCDibraHKarpathakisAFeberANovelliMOukrifDFusaiGValenteRCaplinMMeyerT. Epigenetic dysregulation and poorer outcome in DAXX deficient PNETs. Endocrine-Related Cancer201522L13L18. (doi:10.1530/ERC-15-0108).

97

HuWFengZModicaIKlimstraDSSongLAllenPJBrennanMFLevineAJTangLH. Gene amplifications in well-differentiated pancreatic neuroendocrine tumors inactivate the p53 pathway. Genes & Cancer20101360368. (doi:10.1177/1947601910371979).

98

CaoYGaoZLiLJiangXShanACaiJPengYLiYJiangXHuangX. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nature Communications201342810. (doi:10.1038/ncomms3810).

99

LichtenauerUDDi DalmaziGSlaterEPWielandTKuebartASchmittfullASchwarzmayrTDienerSWieseDThaslerWE. Frequency and clinical correlates of somatic Ying Yang 1 mutations in sporadic insulinomas. Journal of Clinical Endocrinology and Metabolism2015100E776E782. (doi:10.1210/jc.2015-1100).

100

CromerMKChoiMNelson-WilliamsCFonsecaALKunstmanJWKorahRMOvertonJDManeSKenneyBMalchoffCD. Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. PNAS201511240624067. (doi:10.1073/pnas.1503696112).

101

JonkersYMClaessenSMPerrenASchmittAMHoflandLJde HerderWde KrijgerRRVerhofstadAAHermusARKummerJA. DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients. Endocrine-Related Cancer200714769779. (doi:10.1677/ERC-07-0111).

102

DebelenkoLVEmmert-BuckMRZhuangZEpshteynEMoskalukCAJensenRTLiottaLALubenskyIA. The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology1997113773781. (doi:10.1016/S0016-5085(97)70171-9).

103

CaiJLiLYeLJiangXShenLGaoZFangWHuangFSuTZhouY. Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis. Endocrine-Related Cancer2015222333. (doi:10.1530/ERC-14-0225).

104

AgrawalNJiaoYSausenMLearyRBettegowdaCRobertsNJBhanSHoASKhanZBishopJ. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. Journal of Clinical Endocrinology and Metabolism201398E364E369. (doi:10.1210/jc.2012-2703).

105

MouraMMCavacoBMPintoAELeiteV. High prevalence of RAS mutations in RET-negative sporadic medullary thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism201196E863E868. (doi:10.1210/jc.2010-1921).

106

CiampiRMianCFugazzolaLCosciBRomeiCBarolloSCirelloVBotticiVMarconciniGRosaPM. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid2013235057. (doi:10.1089/thy.2012.0207).

107

JiJHOhYLHongMYunJWLeeHWKimDJiYKimDHParkWYShinHT. Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer. PLoS Genetics201511e1005467. (doi:10.1371/journal.pgen.1005467).

108

ShawATKimDWMehraRTanDSFelipEChowLQCamidgeDRVansteenkisteJSharmaSDe PasT. Ceritinib in ALK-rearranged non-small-cell lung cancer. New England Journal of Medicine201437011891197. (doi:10.1056/NEJMoa1311107).

109

SchlisioSKenchappaRSVredeveldLCGeorgeREStewartRGreulichHShahriariKNguyenNVPignyPDahiaPL. The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes and Development200822884893. (doi:10.1101/gad.1648608).

110

WelanderJAndreassonAJuhlinCCWisemanRWBackdahlMHoogALarssonCGimmOSoderkvistP. Rare germline mutations identified by targeted next-generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. Journal of Clinical Endocrinology and Metabolism201499E1352E1360. (doi:10.1210/jc.2013-4375).

111

GaalJBurnichonNKorpershoekERoncelinIBertheratJPlouinPFde KrijgerRRGimenez-RoqueploAPDinjensWN. Isocitrate dehydrogenase mutations are rare in pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism20109512741278. (doi:10.1210/jc.2009-2170).

112

WadtKChoiJChungJYKiilgaardJHeegaardSDrzewieckiKTTrentJMHewittSMHaywardNKGerdesAM. A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma. Pigment Cell & Melanoma Research201225815818. (doi:10.1111/pcmr.12006).

113

LadroueCCarcenacRLeporrierMGadSLe HelloCGalateau-SalleFFeunteunJPouyssegurJRichardSGardieB. PHD2 mutation and congenital erythrocytosis with paraganglioma. New England Journal of Medicine200835926852692. (doi:10.1056/NEJMoa0806277).

114

YangCZhuangZFliednerSMShankavaramUSunMGBullovaPZhuRElkahlounAGKourlasPJMerinoM. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. Journal of Molecular Medicine20159393104. (doi:10.1007/s00109-014-1205-7).

115

CronaJDelgado VerdugoAMaharjanRStalbergPGranbergDHellmanPBjorklundP. Somatic mutations in H-RAS in sporadic pheochromocytoma and paraganglioma identified by exome sequencing. Journal of Clinical Endocrinology and Metabolism201398E1266E1271. (doi:10.1210/jc.2012-4257).

116

OudijkLde KrijgerRRRapaIBeuschleinFde CubasAADei TosAPDinjensWNKorpershoekEMancikovaVMannelliM. H-RAS mutations are restricted to sporadic pheochromocytomas lacking specific clinical or pathological features: data from a multi-institutional series. Journal of Clinical Endocrinology and Metabolism201499E1376E1380. (doi:10.1210/jc.2013-3879).

117

FishbeinLKhareSWubbenhorstBDeSlooverDD'AndreaKMerrillSChoNWGreenbergRAElseTMontoneK. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nature Communications201566140. (doi:10.1038/ncomms7140).

118

PapathomasTOudijkLZwarthoffECPostEDuijkersFAvan NoeselMHoflandLPollardPJMaherERRestucciaDF. TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. Endocrine-Related Cancer201421653661. (doi:10.1530/ERC-13-0429).

119

LiuTBrownTCJuhlinCCAndreassonAWangNBackdahlMHealyJMPrasadMLKorahRCarlingT. The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors. Endocrine-Related Cancer201421427434. (doi:10.1530/ERC-14-0016).

120

JuhlinCCStenmanAHaglundFClarkVEBrownTCBaranoskiJBilguvarKGohGWelanderJSvahnF. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes Chromosomes & Cancer201554542554. (doi:10.1002/gcc.22267).

121

Castro-VegaLJLetouzeEBurnichonNBuffetADisderotPHKhalifaELoriotC