SUN-115 Distinct DNA Methylation Signature in Neuroendocrine Tumors of Different Primary Sites and Hereditary Predisposition

Objective There is scant data of the genome-wide methylome alterations in neuroendocrine tumors (NET). Thus, the goal of this study was to compare the DNA methylation signature of NETs with respect to various primary sites and inherited genetic predisposition syndromes including von Hippel-Lindau (VHL) and multiple endocrine neoplasia type 1 (MEN1). Methods Genome-wide DNA methylation analysis of 96 NETs (primary and metastatic) was performed by using the Illumina Infinium EPIC Array. Principal component analysis (PCA) and unsupervised clustering analyses were performed to identify distinct methylome signatures. The methylation status of genetic drivers such as APC were assessed by primary site. Results A total of 835,424 CpGs methylation sites were quantified. Hypermethylated CpG sites were detected more frequently in sporadic vs. MEN1-related vs. VHL-related NETs, respectively (p < 0.001 for all comparisons), while hypomethylated CpGs sites were more common in VHL-related NETs vs. sporadic and MEN1-related NETs (p<0.001 for both comparisons). Small-intestinal NETs (SINETs) had the most differences at CpGs with the highest number of hyper- and hypomethylated CpG sites, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, p<0.001 for all comparisons). PCA showed distinct clustering of SINETs and three NETs of unknown primary. Sporadic, VHL-related and MEN1-related PNETs formed distinct groups on PCA. VHL-related NETs clustered separately showing pronounced CpG hypomethylation, while sporadic and MEN1-related NETs clustered together showing relative CpG hypermethylation. In a subgroup analysis, MEN1-related SINETs, DNETs and gastric NETs had distinct methylome signatures, respectively, with complete separation by PCA and unsupervised hierarchical clustering. Furthermore, we found CpG hypermethylation in the APC (adenomatous polyposis coli) gene, specifically in the 1A promoter, with higher methylation levels in gastric- and DNETs vs. SINETs, PNETs and NETs of unknown primary (p < 0.001 for all comparisons). Conclusion Various primary NET sites and genetically predisposed MEN1-related NETs have distinct DNA CpG methylation signatures. The methylome signatures identified in this study may be useful for non-invasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or circulating tumor DNA.

Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations

Context.— Familial adenomatous polyposis (FAP) is a rare genetic disorder with autosomal dominant inheritance, defined by numerous adenomatous polyps, which inevitably progress to colorectal carcinoma unless detected and managed early. Greater than 70% of patients with this syndrome also develop extraintestinal manifestations, such as multiple osteomas, dental abnormalities, and a variety of other lesions located throughout the body. These manifestations have historically been subcategorized as Gardner syndrome, Turcot syndrome, or gastric adenocarcinoma and proximal polyposis of the stomach. Recent studies, however, correlate the severity of gastrointestinal disease and the prominence of extraintestinal findings to specific mutations within the adenomatous polyposis coli gene (APC), supporting a spectrum of disease as opposed to subcategorization. Advances in immunohistochemical and molecular techniques shed new light on the origin, classification, and progression risk of different entities associated with FAP. Objective.— To provide a comprehensive clinicopathologic review of neoplastic and nonneoplastic entities associated with FAP syndrome, with emphasis on recent developments in immunohistochemical and molecular profiles of extraintestinal manifestations in the thyroid, skin, soft tissue, bone, central nervous system, liver, and pancreas, and the subsequent changes in classification schemes and risk stratification. Data Sources.— This review will be based on peer-reviewed literature and the authors' experiences. Conclusions.— In this review we will provide an update on the clinicopathologic manifestations, immunohistochemical profiles, molecular features, and prognosis of entities seen in FAP, with a focus on routine recognition and appropriate workup of extraintestinal manifestations.

Compliance with NCCN screening and chemoprevention recommendations among carriers of deleterious mutations in the adenomatous polyposis coli gene.

571 Background: Deleterious mutations in adenomatous polyposis coli gene (APC) lead to familial adenomatous polyposis [FAP] and attenuated FAP (aFAP) syndromes associated with hereditary colorectal cancer (CRC) and extra-colonic neoplasms. Reports suggest only two-third of such patients (pts) comply with recommended screening guidelines. The objective of this study was to assess compliance of FAP/aFAP pts with NCCN recommended guidelines of screening endoscopies and chemoprevention in our population. Methods: Retrospective review of clinical charts of pts with APC mutations, identified through multi-gene panel or single-gene testing, and seen in our NCI designated Comprehensive Cancer Center between 01/2013 and 09/2017. Results: Out of 53 pts with deleterious APC gene mutations, 31 pts (58.5%) had mutations associated with an FAP (27 pts; mean-age 31 years) or aFAP (4 pts, mean-age 33 years) phenotype and were included in analyses. Ten of these 31 pts (32.3%) were diagnosed with FAP after diagnosis of CRC; the rest had family history of FAP/aFAP. Documentation of total-colectomy was found in 17 pts (54.8%), 4 pts (12.9%) did not undergo colectomy and this information was unknown in 10 pts (32.3%). Colonoscopy/EGD after diagnosis of FAP/aFAP was documented in 22 pts (71.1%) while subsequent annual EGD/colonoscopy was documented only in 14 pts (45.1%); records were missing in 13 pts (41.9%). Extra-colonic secondary neoplasms such as duodenal polyps were documented in 8 pts, gastric polyps in 7 pts, desmoid tumor in 2 pts and malignant cancer of ampulla of Vater in 1 pt. Other malignant neoplasms, unrelated with FAP/aFAP, were reported in 3 pts (9.6%, 1 breast, 1 kidney and 1 endometrial cancer). Chemoprevention with sulindac was used in 3 pts (9.7%), 3 pts (9.7%) declined such treatment, 17 pts (54.8%) records were without evidence of this being discussed. Conclusions: The rate of compliance in FAP/aFAP pts with NCCN recommended screening and chemoprevention guidelines in our cohort was low but similar to prior literature. A multidisciplinary approach and interventions to improve compliance among pts are necessary to improve annual screening and chemoprevention rates.