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Joakim Crona and Britt Skogseid

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.

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Samuel Backman, Duska Bajic, Joakim Crona, Per Hellman, Britt Skogseid, and Peter Stålberg


Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1 mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1.


Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 who had negative genetic screening of the MEN1 gene were included.


Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model.


Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson’s two-hit model.


These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

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Joakim Crona, Eric Baudin, Massimo Terzolo, Alexandra Chrisoulidou, Anna Angelousi, Cristina L Ronchi, Cristina Lamas Oliveira, Els J M Nieveen van Dijkum, Filippo Ceccato, Françoise Borson-Chazot, Giuseppe Reimondo, Guido A M Tiberi, Hester Ettaieb, Andreas Kiriakopoulos, Letizia Canu, Darko Kastelan, Esthr Osher, Eugenia Yiannakopoulou, Giorgio Arnaldi, Guillaume Assié, Isabel Paiva, Isabelle Bourdeau, John Newell-Price, Karolina M Nowak, M Tous Romero, Maria Cristina De Martino, Maria João Bugalho, Mark Sherlock, Marie-Christine Vantyghem, Michael Conall Dennedy, Paula Loli, Patrice Rodien, Richard Feelders, Ronald de Krijger, Sam Van Slycke, Simon Aylwin, Valentina Morelli, Laurent Vroonen, Zulfiya Shafigullina, Irina Bancos, Małgorzata Trofimiuk-Müldner, Marcus Quinkler, Michaela Luconi, Matthias Kroiss, Mitsuhide Naruse, Peter Igaz, Radu Mihai, Silvia Della Casa, Alfredo Berruti, Martin Fassnacht, and Felix Beuschlein

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.