GERMLINE PATHOGENIC VARIANTS IN PATIENTS WITH EARLY ONSET NEUROENDOCRINE NEOPLASMS

Introduction: Advances in genetic research have enabled the recognition of new cancer predisposing genes (CPG). Studies have shown that up to 10% of patients (pts) with neuroendocrine neoplasms (NEN) have a hereditary cancer syndrome, with the most common being multiple endocrine neoplasia types I and II and von Hippel Lindau disease. Yet few studies have investigated other CPG in NEN. We aimed to evaluate the frequency of pathogenic and likely pathogenic germline variants (GPV) in known CPG in young adults with NEN and the molecular characteristics of these tumors, such as loss of heterozygosity (LOH) and protein expression. Methods: Pts (without known hereditary cancer syndromes) with lung or digestive NEN diagnosed between 18 to 45 years were prospectively recruited. Constitutive DNA was extracted from saliva or blood. Germline variants were screened by NGS using a custom 113 gene panel in an Illumina NextSeq 500. Variant calling and interpretation were performed using both in house and commercial softwares, and variant classification was performed following the ACMG guidelines. For GPV, amplicon sequencing was performed in tumor DNA to identify LOH; NGS and PCR were used to evaluate tumor genomic alterations in pts with GPV. Results: From Jun/2019 to Ap/2021, 108 pts were enrolled and 17 (15.7%; 95% confidence interval [CI]: 8.9% – 22.6%) presented at least one heterozygous GPV. Median age, sex, stage at diagnosis, family history of NEN or any personal history of neoplasm were similar between patients with or without GPV. GPV carriers had more gastric (p = 0.084) and functioning NEN (p = 0.041), positive family history of cancer (any relative; 88.2% vs 57.1%; p = 0.015). and exclusively well-differentiated NEN. Genes affected were mostly involved in DNA repair (CHEK2, ERCC2, ERCC3, XPC, MSH6, POLE, SLX4), with most GPV found in MUTYH. Six cases had a first-degree relative with NEN. LOH was performed in 8 cases; a second hit event in SLX4 was suggested in one case (variant allele frequency of 73%) Conclusions: Young adults with NEN present a high rate of GPV in CPG, mostly in DNA repair genes. These pts more often had a family history of cancer and functioning NEN.