SUN-046 Identification of Clinical Predictors for Detection of Mutations in Multiple Endocrine Neoplasia Type 1

Abstract

Context: Guidelines has systematically suggested genetic testing for a wide spectrum of phenotypes in order to confirm or exclude surely the diagnosis of multiple endocrine neoplasia type 1 (MEN1). However, the probability of find a germline MEN1 mutation has showed extremely variable (5-95%) when different phenotypes are considered. The prompt recognition of potential clinical predictors could anticipate the result of the genetic testing in the different clinical scenarios. Objective: To investigate if specific phenotypic features may predict the presence of germline MEN1 mutations in index-cases with clinical diagnosis of MEN1 syndrome. Methods and Patients: 110 MEN1 index cases were included: amplicons based on long-range PCR covering the full MEN1 open reading frame of 94 MEN1 index cases (49 familial, 45 sporadic) were sequenced by targeted-Next Generation Sequencing (tNGS) MiSeq Illumina platform while Sanger Sequencing (SS) was approached to the other 16 MEN1 index cases (2 familial, 14 sporadic). MLPA assay was supported to 31 MEN1-negative patients by tNGS/SS whose DNA samples were available. Results: 68 index cases (62%) had germline MEN1 mutations. With the tNGS/SS/MLPA protocol, the mutation detectability rate was higher in familial MEN1 (90%, 46/51 vs. 37%; 22/59; p, < 0.05). In comparison with MEN1-positive patients, MEN1-negative cases were older (53±12 vs. 39±13; p, < 0.05) and most of them had no more than two MEN1-related tumors (76%, 32/42 vs. 10%, 7/68; p, < 0.05). Considering the subset of 59 patients with negative familial history, the 22 MEN1-positive patients revealed clinical predictors for detection of MEN1 mutation when they were compared with 37 truly non-MEN1 mutation carriers. Thus, sporadic MEN1-positive patients had higher significantly prevalence of the following predictors. 1) ≥ 3 tumors, 86% (19/22) versus 11% (4/37); 2) PETs, 86% (19/22) versus 22% (8/37); 3) which were multifocal, 100% versus 1/8 (9%); 4) with frequent synchronic association of functioning and NF/PETs, 47% (9/19) versus 0% and; 5) high frequency of malignancies, 58% (11/19) versus 5% (2/37). Indeed, there was confirmation of these predictors comparing all 68 MEN1-positive carriers against 42 MEN1-negative cases. Conclusions: The strategy adopted to support the diagnosis of MEN1 based on analysis of clinical predictors and genetic testing for tNGS/SS-MLPA underscored that the positive familial history, occurrence of three or more MEN1 tumors, presence of PETs, especially multifocal PETs, and malignancies are strong predictors to detection of MEN1 mutations.