Objective: Multiple endocrine neoplasia type 1 (MEN1) is a rare heritable tumor syndrome caused by germline mutations of MEN1 gene affecting mainly the parathyroid, pituitary and pancreas. Phenotype varies widely, even in first-degree relatives. Recently it has been shown that functionally active gastroenteropancreatic neuroendocrine tumors (GEP-NETs), initially frequently diagnosed as sporadic cases, lead to MEN1 diagnosis. Non-functioning tumors are increasingly recognised due to advanced imaging modalities such as endoscopic ultrasound and thus became the most common GEP-NET in MEN1 patients. Contrary to sporadic GEP-NETs, MEN1-associated cases are diagnosed 10 years earlier and their penetrance is as high as 80-90%, reaching nearly that of the parathyroid adenomas. Mutation analysis enables early tumor detection, thus the possibility to prevent serious, even life-threatening morbidities associated with malignant GEP-NET. Our aim was to identify phenotype features predictive for a positive MEN1 genetic test, and by comparing mutation-positive and mutation-negative patients to evaulate the role of MEN1 mutations in phenotype modulation.
Design and methods: Of the 104 probands who fulfilled the criteria of MEN1 mutation analysis, 36 patients with GEP-NET were enrolled in this study. Mutation screeening of the MEN1 gene by Sanger sequencing was performed at our national reference laboratory. Clinical data were studied together with laboratory, imaging and histological results. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases.
Results: Of 36 GEP-NET patients mutation analysis demonstrated disease-causing mutation in 19 patients. GEP-NET developed significantly earlier in mutation-positive patients; more than half of them appeared under 30 years of age. The prevalence of GEP-NET was also significantly higher at initial presentation in mutation carriers compared to mutation negative patients. The presence of GEP-NET under 30 years best predicted a positive MEN1 genetic test. Its prevalence remained significantly higher among mutation carriers during the follow-up. In addition, probands with high-impact mutations (frameshift, nonsense, large deletions), predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers.
Conclusions: GEP-NETs appear significantly earlier and more frequently in MEN1-positive patients and best predicted a positive genetic test. MEN1 patients with high-impact mutations were more likely to develop GEP-NETs, revealing a possibly important prognostic consequences regarding genetic counseling.
19 May 2018 - 22 May 2018