RAD51B Harbors Germline Mutations Associated With Pancreatic Ductal Adenocarcinoma.

Abstract

Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond <i>BRCA1</i>, <i>BRCA2</i>, <i>ATM</i>, and <i>PALB2</i> may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC). We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores. Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with <i>BRCA2</i> mutations is associated with a high HRD score. However, another tumor with a <i>CHEK2</i> mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a <i>RAD51B</i> gene mutation. All four <i>RAD51B</i> gene mutations were germline mutations. However, currently, <i>RAD51B</i> is not the gene panel for germline tests. The finding in this study thus supports including <i>RAD51B</i> in the germline test of HR-DDR pathway genes.