Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer

TLDR

Pancreatic cancer is projected to become the second leading cause of cancer‑related death in the United States by 2020, and although familial aggregation is established, the cause of this aggregation in most families remains unknown. The study aimed to uncover the genetic basis of susceptibility in familial pancreatic cancer. The authors sequenced germline genomes of 638 familial pancreatic cancer patients and tumor exomes of 39 familial pancreatic adenocarcinomas, and demonstrated that somatic point mutations arising during hematopoiesis can confound genome‑wide studies of hereditary traits. Analyses confirmed known susceptibility genes (BRCA2, CDKN2A, ATM) and identified novel candidate genes with rare deleterious germline variants, revealing that inherited pancreatic cancer is highly heterogeneous and has implications for disease etiology, management, and susceptibility gene discovery in other cancers.

Abstract

Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types.The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.