Whole genomes redefine the mutational landscape of pancreatic cancer

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded. A whole-genome sequencing analysis of 100 pancreatic ductal adenocarcinomas has discovered known and newly identified genetic drivers of pancreatic cancer; these genetic alterations can be classified into four subtypes, which raises the possibility of improved targeting of clinical treatments. A whole-genome sequencing analysis of 100 pancreatic ductal adenocarcinomas has revealed known and newly identified genetic drivers of pancreatic carcinogenesis. These genetic alterations can be classified into four subtypes based on the patterns of structural variation — stable, locally rearranged, scattered and unstable — which raises the possibility of improved targeting of clinical treatments. A number of tumours harboured focal amplifications, many containing druggable oncogenes, although at low individual prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes and a mutational signature of DNA damage repair deficiency. In a proof-of-concept study, the authors show the potential utility of these genomic signatures as putative biomarkers for therapeutic selection.