Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

in European Journal of Endocrinology

Objective

To investigate whether congenital IGF1 deficiency confers protection against development of malignancies, by comparing the prevalence of malignancies in patients with congenital (secondary) deficiency of IGF1 with the prevalence of cancer in their family members.

Method

Only patients with an ascertained diagnosis of either Laron syndrome (LS), congenital IGHD, congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were included in this study. In addition to our own patients, we performed a worldwide survey and collected data on a total of 538 patients, 752 of their first-degree family members, of which 274 were siblings and 131 were further family members.

Results

We found that none of the 230 LS patients developed cancer and that only 1 out of 116 patients with congenital IGHD, also suffering from xeroderma pigmentosum, had a malignancy. Out of 79 patients with GHRHR defects and out of 113 patients with congenital MPHD, we found three patients with cancer in each group.

Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found 30 cases of cancer and 1 suspected. In addition, 31 malignancies were reported among 131 further relatives.

Conclusions

Our findings bear heavily on the relationship between GH/IGF1 and cancer. Homozygous patients with congenital IGF1 deficiency and insensitivity to GH such as LS seem protected from future cancer development, even if treated by IGF1. Patients with congenital IGHD also seem protected.

Abstract

Objective

To investigate whether congenital IGF1 deficiency confers protection against development of malignancies, by comparing the prevalence of malignancies in patients with congenital (secondary) deficiency of IGF1 with the prevalence of cancer in their family members.

Method

Only patients with an ascertained diagnosis of either Laron syndrome (LS), congenital IGHD, congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were included in this study. In addition to our own patients, we performed a worldwide survey and collected data on a total of 538 patients, 752 of their first-degree family members, of which 274 were siblings and 131 were further family members.

Results

We found that none of the 230 LS patients developed cancer and that only 1 out of 116 patients with congenital IGHD, also suffering from xeroderma pigmentosum, had a malignancy. Out of 79 patients with GHRHR defects and out of 113 patients with congenital MPHD, we found three patients with cancer in each group.

Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found 30 cases of cancer and 1 suspected. In addition, 31 malignancies were reported among 131 further relatives.

Conclusions

Our findings bear heavily on the relationship between GH/IGF1 and cancer. Homozygous patients with congenital IGF1 deficiency and insensitivity to GH such as LS seem protected from future cancer development, even if treated by IGF1. Patients with congenital IGHD also seem protected.

Introduction

Linked to their proliferative, differentiation and apoptotic properties, both GH and insulin-like growth factor 1 (IGF1) have been identified as risk factors for certain malignancies (1, 2, 3, 4, 5), even in the pediatric age group and young adults (6, 7, 8). There is also evidence that most tumors and transformed cells display increased IGF1 receptor (IGF-1R) concentration and high IGF1R mRNA, causing enhanced IGF1 binding (9, 10), leading to the axiom that overexpression of IGF1R is a pre-requirement for acquisition or progress of malignant tumors (11). Further evidence for the link between GH, IGF1 and cancer is the successful use of GH and IGF-1R-blocking agents in the treatment of malignancy (12). The above findings led us to investigate the reverse situation, namely whether congenital defects of GH and IGF1 action would diminish or prevent the development of cancer.

In 2007, we reported preliminary data on 169 patients with Laron syndrome (LS) and on 250 of their first- and second-degree relatives and found that none of the homozygous LS patients had developed cancer, whereas 24% of their heterozygous family members had (13). We also showed that 35 patients with congenital (c) IGHD and 18 with GHRH receptor (R) mutation reported no malignancies. In contradiction, 9–24% of their family members had a history of cancer.

The aim of the present study was to extend our findings by enlarging the number of patients with LS and cIGHD and to collect data on patients with GHRHR mutations and congenital multiple pituitary hormone deficiency (cMPHD), including GH.

Methods

This retrospective study was approved by the ethics committee. The following procedures were employed to collect the data:

  • We updated data from our medical charts of LS patients, which had increased to 67 and, 28 patients were with cIGHD.

  • Sent questionnaires to authors of published reports on patients with the diagnoses mentioned.

  • Approached personally the physicians from countries we knew there are patients with the above diseases.

Out of the several hundreds of questionnaires sent, we received replies from over 80 colleagues. The limitations found in collecting the data were:

  • Some of the authors reporting the patients had performed only the genetic analysis and had no clinical information on the patients.

  • Many of the patients live in small villages and countries inaccesible to the treatment, so patient follow-up was lost. Prevalence of cancer types could also not be obtained from these countries.

  • Lack of cooperation.

Statistical analysis

The collected data were analysed using the BMDP statistical software (14). One-way and two-way ANOVA were used to analyse continuous variables (age) and as for discrete variables (diagnosis/type of malignancy), χ2 test and Fisher's Exact test were used. A P value <0.05 was considered statistically significant.

Subjects

We were able to collect data on a total of 538 patients, 752 of their first-degree family members (parents, siblings and offspring) and 131 further family members. Only patients with the following ascertained diagnoses were included in this study:

  • LS – secondary congenital deficiency of IGF1 and primary GH insensitivity, due to defects in the GH receptor.

  • Primary congenital isolated hGH deficiency (cIGHD).

  • GHRHReceptor (R) defect – secondary hGH deficiency.

  • Congenital multiple pituitary hormone deficiency, including hGH (cMPHD).

A high percentage of the LS, cIGHD and GHRHR patients underwent genetic molecular analysis. In most of the cMPHD patients, the diagnosis was based on clinical and endocrine evaluation. Unfortunately, the ages were not stated for all patients and relatives, nor was the age of diagnosis of malignancies stated in all questionnaires.

Results

Table 1 shows the number and age distribution of patients as well as that of the first-degree relatives, including siblings and further relatives in each diagnostic group. It is of note that we were able to collect data on half or more of the presumed total number of LS patients (not including the Ecuadorian cohort) and probably a large percentage of those with GHRHR mutations.

Table 1

Number and age of the patients and their relatives in four diagnostic groups with secondary congenital IGF1 deficiency.

Diagnostic groups
Laron syndrome (GHR defects)cIGHDGHRHR defectcMPHDTotal
Patients
 Total number (n)23011679113538
 Number with known age166a106b16c113d401e
 Age range1–751.5–552.8–880.25–870.25–87
 Mean age±s.d.19.2±1518.3±12.829.7±2329.4±18.722.2±16.7
First-degree relatives
 Total number (n)218203150181752
 Number with known age15720012173542
 Age range1–811–843–931–841–93
 Mean age±s.d.37.7±19.132.2±19.148±2431.4±18.533.8±19.3
Further relatives
 Total number (n)1131341131
 Number with known age38124
 Age range29–8528–8326–5926–85
 Mean age±s.d.61±14.761.83±17.943.2±17.159.8±16
Siblings only
 Total number (n)8696686274
 Number with known age6595683249
 Age range1–801–813–471–561–81
 Mean age±s.d.25.7±17.322.2±1936.3±16.619.2±13.322.4±17
P values
 Patients versus first-degree relatives<0.001<0.0010.030.37<0.001
 Patients versus siblings0.0010.080.49<0.0010.7

Number of patients above 30 years: a31; b19; c6; d51; e107.

In total, the patients were significantly younger than their first-degree relatives (P<0.001), though the differences in the GHRHR defect and the cMPHD groups were not significant. Also, there was no significant age difference when we compared the age of patients with that of their siblings. It is worth mentioning that the patients' age range was wide, reaching 85 years, and that 25% of the patients with recorded age were above 30 years of age.

Table 2 shows the prevalence of malignancies in the patients and their relatives in each diagnostic group. It is seen that none of the 230 LS patients had developed a malignancy, despite the fact that 66 had been or are still treated by IGF1 and two had received hGH as well. The difference between the prevalence of malignancies in all the first-degree relatives and that in the siblings alone, with that in the patients was significant (P<0.001, P=0.005, respectively). Out of the 116 patients with cIGHD, only one boy suffers from xeroderma pigmentosum was reported to have a basal cell carcinoma (BCC) diagnosed at the age of 15 years. Fifty-nine of cIGHD patients had been treated with hGH, including the boy who developed BCC. Out of the 79 patients with GHRHR mutations (12 previously treated with hGH), three had cancer (one of them previously treated with hGH) and so had three out of 113 patients with cMPHD. In the latter group, 97 had been previously treated with hGH, in addition to other hormone replacement therapy, and among them, two had developed malignancies.

Table 2

The prevalence of malignancy in the four diagnostic groups.

Diagnostic groups
Laron sydromecIGHDGHRHR defectscMPHDTotal
Patients
 Total number (n)23011679113538
 Number of malignancies01b3c3d7
 Prevalence of malignancy (%)0.00.93.82.71.3
First-degree relatives
 Total number (n)218203150181752
 Number of malignancies18 (15)7 (6)05+1a (6)30 (26+1)a
 Prevalence of malignancy (%)8.33.40.02.84.0
Further relatives
 Total number (n)1131341131
 Number of malignancies25 (24)4 (4)1 (1)1 (1)31 (30)
 Prevalence of malignancy (%)22.130.82523.7
Siblings only
 Total number (n)8696686274
 Number of malignancies5 (4)2 (2)02 (2)9 (80)
 Prevalence of malignancy (%)5.82.10.02.33.3
P values
 Patients versus first-degree relatives<0.0010.430.0410.019
 Patients versus further relatives<0.001<0.0010.182<0.001
 Patients versus siblings0.0050.5911<0.165

Number in parentheses indicate number of individuals. aIndicates one suspected malignancy; bincludes one male basal cell carcinoma diagnosed at 15 years; cincludes one male Hodgkins lymphoma diagnosed at 43 years and two male skin cancers (one diagnosed at 37 years and the other unknown); dincludes two female thyroid carcinoma diagnosed at 10.5 and 52 years and one male planocellular carcinoma of the nasal septum diagnosed at 66 years of age.

Out of 752 first-degree relatives, 26 reported 30 instances of cancer (P=0.019) and out of 131 further relatives, 30 reported 31 instances of cancer (P<0.001). Nine malignancies were reported in eight of the siblings (P=0.165). In Table 3, it is evident that the majority are lung, breast and prostate cancer, followed by colon and gastric cancer.

Table 3

Types of cancer reported in first and further-degree relatives of patients with congenital insulin-like growth factor 1 deficiency.

Type of cancerNumber (age at diagnosis in years)Diagnosis of probands
Lung9 (48–72)7 LS, 1 IGHD, 1, MPHD
Breast7 (45–75)5 LS, 2 IGHD
Prostate7 (40–76)6 LS, 1 IGHD
Colon6 (58–63)3 LS, 3 IGHD
Gastric6 (43, unk.)4 LS, 1 IGHD, 1 MPHD
Leukemia4 (3–84)2 LS, 1 MPHD, 1 GHRHR defect
Unknown primary4 (unk.)3 LS, 1 IGHD
Pancreas2 (54, 73)1 LS, 1 MPHD
Uterus2 (48, unk.)2 LS
Bone2 (17, unk.)1 IGHD, 1 MPHD
Lymphoma2 (62, unk.)1 IGHD, 1 MPHD
Nose1 (unk.)1 LS
Renal1 (unk.)1 LS
Thyroid1 (25)1 LS
SCC1 (65)1 LS
Brain2 (4, 56)+1 susp. (13)2 LS (susp. – MPHD)
Liver1 (unk.)1 LS
Esophagus1 (unk.)1 LS
Bladder1 (81)1 LS
Testis1 (unk.)1 LS
Total61 malig. +1 susp.

UNK, unknown.

Discussion

In this attempt of a worldwide survey of the prevalence of cancer in patients with secondary congenital IGF1 deficiency, we confirmed and enlarged our preliminary observation that patients with LS, having both congenital GH and IGF1 deficiency and insensitivity to endogenous and exogenous GH, seem protected from the development of cancer (13). That observation was also confirmed by findings in the large Ecuadorian cohort of LS patients (15). Considering that the latter cohort accounts for 100 living patients, it is obvious that over 300 patients with LS, the majority now being adults, have not developed cancer.

In contradistinction, 15 of their 218 first-degree relatives in the present survey and 24 out of 131 further relatives (proven or supposed heterozygotes for the disease) reported 43 instances of cancer. The difference between presence or absence of malignancy between patients with LS and their first-degree relatives and siblings was statistically significant (P<0.001, P=0.005, respectively). In the Ecuadorian cohort, 80 out of 1032 relatives died of cancer (15).

Only one boy out of 116 patients with congenital IGHD presented a BCC of the cheek. This patient also suffered from xeroderma pigmentosum, a genetic defect involving DNA repair. Out of the 79 patients with GHRHR mutation and 113 with congenital MPHD, six instances of cancer were reported, three with previous hGH treatment.

The lack of complete protection against cancer in the patients with GHRHR mutations and those with congenital MPHD could be due either to the fact that some patients still secrete small amounts of GH (16), that some are sensitive to the exogenously administered hGH treatment or other environmental noxae and/or belonging to a familial genetic trend for malignancy.

The fact that heterozygote family members, which secrete IGF1 and/or hGH, develop malignancies, in a relatively high incidence for the given ethnic groups, may favor the above assumption. It is also of note that the types of malignancies and their prevalence in our study group correspond to the prevalence in the overall population (17).

The difference in age range between the patients who did not develop cancer and the family members who developed cancer may be considered to influence our conclusions, although our own cohort of 67 LS and 28 cIGHD patients consists almost entirely of adult patients, pointing to the fact that age may be a confounding factor but not the major factor in the development of cancer. Comparing our data with the incidence of cancer in Israel and neighboring countries, it is evident that the incidence in the age group 0–19 years is 10% of that occurring in the age group 20–49 years. In these populations, breast cancer is diagnosed as early as 15 years (The web site of the Israeli National Cancer Registry, www.health.gov.il/icr).

The present reported clinical data is supported by recent animal experiments which prove that the homozygous GHR-KO-mouse (18, 19) exhibits statistically significant reductions in the overall incidence of malignancy (20, 21, 22). An earlier experimental study also revealed that dw/dw rats, congenitally deficient in GH, are resistant to dimethylbenzathracene (DMBA)-induced mammary carcinoma (23).

It is of interest that animal experiments with cMPHD mice (Ames and Snell) have shown different degrees of protection against malignancies. While the Snell mice exhibit significant protection against the development of cancer (24), the Ames mice are not different from their litter mates regarding the prevalence of malignancies, but develop the cancer at an older age (25). This resembles our data in man and is possibly due to the secretion of small amounts of GH. Further support for our hypothesis that IGF deficiency tends to protect against cancer is the successful use in oncology of IGF1R-blocking drugs (12).

In conclusion, our findings bear heavily on the relationship between GH/IGF1 and cancer. Follow-up of the homozygous patients with congenital IGF1 deficiency and insensitivity to GH will show whether they are protected from future cancer development, even if treated with IGF1. Patients with congenital IGHD, nowadays treated with hGH in most countries, also seem protected (the only instance of cancer reported needs further clarification).

The secretion of small amounts of endogenous GH/IGF1 such as that shown in few patients with GHRHR mutation or with congenital MPHD, as well as their normal secretion in heterozygous carriers of LS or IGHD gene defects, may play a role in the development of cancer in these patients.

Declaration of interest

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

Funding

This research was part of the Thesis of R Steuerman as part of the requirements toward the MD degree at the Sackler Faculty of Medicine, Tel-Aviv University.

Acknowledgements

We are indebted to the following colleagues for providing data on their patients: Gianluca Aimareti, Italy; A Akinci, Turkey; Ivo Arnhold, Brazil; Simon Attard-Montalto, Malta; B Ayudant, Peru; Maryam Razzaghy Azar, Iran; Carlos Ben-Basat, Israel; Merih Berberoglu, Turkey; Carla Bizzari, Italy; Gianfranco F Bottazo, Italy; George Bright, USA; Thierry Brue, France, Atilla Buyukgebitz, Turkey; Marco Cappa, Italy; Luciani Carvalho, Brazil; Fernando Cassorla, Chile; Shelly Chen, China; Amnon Cohen, Italy; Chris Cowell, Australia; Patricia Crock, Australia; Feyza Darendeliler, Turkey; Filippo De Luca, Italy; Carlo De Sanctis, Italy; Liat De-Vries, Israel; Alon Eliakim, Israel; Mohamed El Kholy, Egypt; Betul Ersoy, Turkey; Angel Ferrandez Longas, Spain; Herwig Frisch, Austria; Vivian Gallardo, Chile; Assimina Galli-Tsinopoulou, Greece; Ezio Ghigo, Italy; Rachel Gurevich, Israel; Elke Hammer, Germany; Fatima Harun, Malaysia; Harry Hirsch, Israel; Ali Hojjat, UK; Reiko Horikawa, Japan; Vivian Hwa, USA; Lourdes Ibanez, Spain; Keiji Iida, Japan; Alexander Jorge, Brazil; Alexandra Keller, Germany; Ciril Krzisnik, Slovenia; Banu Kucukemre, Turkey; Angelico Lampis, Italy; Liora Lazar, Israel; Kwok Leung, Hong Kong; Yael Levental-Bendor, Israel; Yehuda Limoni, Israel; Mare Maes, Belgium; Manuel Herminio Aguiar-Oliviera, Brazil; Alicia Martinez, Argentina; Maria Francesco Messina, Italy; Dalit Modan, Israel; Primus Mullis, Switzerland; Osamu Nose, Japan; Oswaldo Nunez, Peru; Zerrin Orbak, Turkey; Alev Ozon, Turkey; Magdalena Paskova, Slovakia; Moshe Phillip, Israel; K Pichestin, Thailand; Mariana Rachmiel, Israel; Yardena Rakover-Tennenbaum, Israel; Ron Rosenfeld, USA; Roberto Salvatori, USA; Jeerunda Santiprabhob, Thailand; Lars Savendahl, Sweden; Antonio Selman, Santo Domingo; Stephan Shalet, UK; Shuixian Shen, China; Ivani Novato Silva, Brazil; Phyllis Speiser, USA; Maithe Tauber, France; Svetlana Ten, USA; M Tibi, Israel; Dov Tiosano, Israel; Rahim Vakili, Iran; M Vera, Cuba; J Vesterhus, Norway; Saria Wakim, Lebanon; Marie-Jose Walenkamp, Netherlands; Hartmut Wollmann, Germany; N Yordam, Turkey; Stefano Zucchini, Italy. We also wish to acknowledge Mrs Pearl Lilos for her assistance in the statistical calculations.

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References

  • 1

    PandeyVPerryJKMohankumarKMKongXJLiuSMWuZSMitchellMDZhuTLobiePE. Autocrine human growth hormone stimulates oncogenicity of endometrial carcinoma cells. Endocrinology200814939093919doi:10.1210/en.2008-0286.

    • Search Google Scholar
    • Export Citation
  • 2

    DardenneMSmaniottoSde Mello-CoelhoVVilla-VerdeDMSavinoW. Growth hormone modulates migration of developing T cells. Annals of the New York Academy of Sciences2009115315doi:10.1111/j.1749-6632.2008.03977.x.

    • Search Google Scholar
    • Export Citation
  • 3

    FurstenbergerGSennHJ. Insulin like growth factors and cancer. Lancet Oncology20023298302doi:10.1016/S1470-2045(02)00731-3.

  • 4

    FrascaSPandiniGSciacciLPezzinoVSquatritoSBelfioreAVigneriR. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Archives of Physiology and Biochemistry20081142337doi:10.1080/13813450801969715.

    • Search Google Scholar
    • Export Citation
  • 5

    Pollak MN. Insulin like growth factors and neoplasia. In Biology of IGF-I: Its Interaction with Insulin in Health and Malignant States pp 84–107. Chichester: Wiley Novartis foundation symposium 262 2004.

  • 6

    BalamuthNJWomerRB. Ewing's sarcoma. Lancet Oncology201011184192doi:10.1016/S1470-2045(09)70286-4.

  • 7

    NatrajanRReis-FilhoJSLittleSEMessahelBBrundlerMADomeJSGrundyPEVujanicGMPritchard-JonesKJonesC. Blastemal expression of type I insulin-like growth factor receptor in Wilms' tumors is driven by increased copy number and correlates with relapse. Cancer Research2006661114811155doi:10.1158/0008-5472.CAN-06-1931.

    • Search Google Scholar
    • Export Citation
  • 8

    HoughtonPJMortonCLGorlickRKolbEAKeirSTReynoldsCPKangMHMarisJMWuJSmithMA. Initial testing of a monoclonal antibody (IMC-A12) against IGF1R by the pediatric preclinical testing program. Pediatric Blood and Cancer201054921926doi:10.1002/pbc.22367.

    • Search Google Scholar
    • Export Citation
  • 9

    EshetRWernerHKlingerBSilbergeldALaronZLeroithDRobertsCT. Up-regulation of insulin-like growth factor-I (IGF-I) receptor gene expression in patients with reduced serum IGF-I levels. Journal of Molecular Endocrinology199310115120doi:10.1677/jme.0.0100115.

    • Search Google Scholar
    • Export Citation
  • 10

    WernerHLeRoithD. The insulin-like factor-I receptor signaling pathways are important for tumorigenesis and inhibition of apoptosis. Critical Reviews in Oncology/Hematology199787192.

    • Search Google Scholar
    • Export Citation
  • 11

    WernerH. The pathophysiological significance of IGF-I receptor overexpression: new insights. Pediatric Endocrinology Reviews2009725.

  • 12

    AtzoriFTrainaTAIontaMTMassiddaB. Targeting insulin-like growth factor type 1 receptor in cancer therapy. Targeted Oncology20094255266doi:10.1007/s11523-009-0123-z.

    • Search Google Scholar
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