Germline Pathogenic Variants in Homologous Recombination Pathway Genes Are Frequent in Pancreatobiliary Ampullary Carcinoma.

Abstract

Ampullary carcinoma (AMPCA) is a rare cancer classified into subtypes depending on the histologic appearance and epithelium of origin. To gain insights into the germline genetic factors driving predisposition to AMPCA, the analysis focused on the role of homologous recombination (HR) genes in its oncogenesis. We analyzed germline testing results from 26,159 patients with cancer undergoing clinical tumor-normal sequencing from May 2015 to November 2022, of which 112 individuals had AMPCA. Germline and somatic alteration profiles were analyzed for the different histologic subtypes of AMPCA, and a subset of cases were selected for whole-genome sequencing (WGS) to determine the presence of HR deficiency (HRD). Pathogenic variants in HR pathway genes were identified in 17/72 (23.6%), 0/26 (0.0%), and 1/14 (7.1%) patients with pancreatobiliary (PAMPCA), intestinal (IAMPCA), and other (mixed, neuroendocrine, adenosquamous) subtypes of AMPCA, respectively. Germline pathogenic variants in core HR genes, including <i>BRCA1</i>, <i>BRCA2</i>, and <i>PALB2</i>, were exclusively detected in the PAMPCAs, and one <i>ATM</i> germline pathogenic variant was detected in a case with mixed intestinal and pancreatobiliary features. HRD features were detected in all four representative PAMPCA tumor samples that underwent WGS and HRDetect analysis. Germline pathogenic variants in the HR pathway genes drive oncogenesis in a large subset of PAMPCAs. These findings highlight the importance of germline genetic testing for patients with PAMPCA for informing therapy and assessing familial risk.