Widespread somatic loss of heterozygosity as a possible marker of disease aggressiveness in metastatic well differentiated pancreatic neuroendocrine tumors.

Abstract

275 Background: To assess the utility of molecular profiling to predict tumor biology, we performed next-generation sequencing (NGS) of metastatic well differentiated (WD) pancreatic neuroendocrine tumors (panNETs) in the routine practice setting. Our institutional NGS platform allows for evaluation of genetic alterations that contribute to tumorigenesis (sequence variants, copy number alterations, insertions/deletions, select rearrangements) as well as somatic loss of heterozygosity (LOH). Methods: NGS was performed using MSK-IMPACT, a matched tumor-normal sequencing platform that interrogates 468 cancer-related genes. LOH for all cases was determined by analysis of total, allele-specific, and integer DNA copy number genome-wide using the FACETS algorithm. Results: Since 2014, NGS has been performed in 96 tumor samples from 80 patients. The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). LOH was highly prevalent, identified in 51/96 samples (53%). A significant association (q-value < 0.05) was noted between LOH and the presence of altered MEN1, DAXX, PTEN, or TSC2. LOH was recurrently observed in chromosomes 1, 2, 3, 6, 8, 10, 11, 15, 16, 21, and 22. Since MEN1 alterations predict improved outcome, comparison was made between patients with LOH present/MEN1 wild type (WT) tumors (n = 16) and LOH absent/MEN1 altered tumors (n = 21); inferior overall survival (OS) was noted with LOH present/MEN1 WT status (p < 0.01). High grade pathology was observed in 6/16 (38%) LOH present/MEN1 WT tumors and in 1/21 (5%) LOH absent/MEN1 altered tumors (p < 0.0001). The mean Ki-67 index of LOH present/MEN1 WT tumors was 22% and that of LOH absent/MEN1 altered tumors was 9%. Conclusions: This is the first study to report widespread somatic LOH in metastatic WD panNETs. PanNETs appear to exhibit more LOH overall than virtually any tumor type studied. In this cohort, LOH was a prognostic marker of inferior OS and was associated with more aggressive pathologic features. LOH warrants further investigation as it may help better characterize these clinically heterogeneous tumors.