Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole genome sequencing and CNV analysis of 100 pancreatic ductal adenocarcinomas. Chromosomal rearrangements leading to gene disruption were frequent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A, ROBO2) and novel candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation classified PDAC into 4 subtypes with potential clinical utility: 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 frequency. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2, PALB2 or RPA1), and a mutational signature of DNA damage repair deficiency. This subgroup was associated with response to platinum-based therapy and defines candidate biomarkers of therapeutic responsiveness.
Overall design
DNA was assayed using Illumina SNP BeadChips as per manufacturer’s instructions (Illumina, San Diego CA) (HumanOmni1-Quad or HumanOmni2.5-8 BeadChips). SNP arrays were scanned and data was processed using the Genotyping module (v1.8.4) in Genomestudio v2010.3 (Illumina, San Diego CA) to calculate B-allele frequencies (BAF) and logR values. GenoCN4 and GAP5 were used to call somatic regions of copy number change – gain, loss or copy neutral LOH. Recurrent regions of copy number change were determined and genes within these regions were extracted using ENSEMBL v70 annotations. Significant regions of gain and loss were identified by GISTIC6.
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