Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients

• Published in: Annals of human genetics Vol. 86; no. 4; pp. 195 - 206
• Main Authors: Tan, Ming, Brusgaard, Klaus, Gerdes, Anne‐Marie, Larsen, Martin Jakob, Mortensen, Michael Bau, Detlefsen, Sönke, Muckadell, Ove B. Schaffalitzky, Joergensen, Maiken Thyregod
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2022; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Association analysis; BRCA2 protein; Extracellular matrix; familial pancreatic cancers; Genetic diversity; Genomes; Original; Pancreatic cancer; pancreatic ductal adenocarcinoma; Paraffin; protein truncating variants; rare variants; Whole genome sequencing; rare variants; whole genome sequencing; protein truncating variants; familial pancreatic cancers; pancreatic ductal adenocarcinoma
• ISSN: 0003-4800; 1469-1809
• DOI: 10.1111/ahg.12464

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies with very high mortality and short survival time. About 5–10% of the PDAC patients have a familial predisposition to the disease designated as familial pancreatic cancer (FPC), suggesting genetic modulation of FPC pathogenesis. It is estimated that currently identified sequence variants account for less than 20% of the genetic basis of FPC leaving the majority of the genetic architecture unclarified. We performed whole genome sequencing (WGS) analysis on benign formalin‐fixed paraffin‐embedded (FFPE) tissues from 35 FPC patients focusing on genes enriched by rare and functional sequence variants. We identified 40 genes hosting at least 2 protein truncating variants (PTVs). Significant overlaps of the 40 genes were found (p < 1 × 10–22) with cancer genes, cancer driver genes and genes found in previous studies on cancer, including ATM, POLE, BRCA2, TYR03, PABPC1 and SSC5D. The PTV genes are significantly overrepresented in biological pathways in cancer development and progression including extracellular matrix organization, signaling by RHO GTPases and RHO GTPase cycle. Association analysis using external controls detected 6 genes with p < 0.05. The WGS analysis revealed high heterogeneity in the detected rare variants among FPC patients and provides novel genes harboring potential mutational hotspots for future validation and replication.