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      Whole genomes redefine the mutational landscape of pancreatic cancer.

      Nature

      antagonists & inhibitors, Poly(ADP-ribose) Polymerases, genetics, Point Mutation, pharmacology, Platinum, drug therapy, classification, Pancreatic Neoplasms, Mutation, Mice, Humans, Genotype, Genomics, Genomic Instability, Genome, Human, Genetic Markers, Genes, BRCA2, Genes, BRCA1, Female, DNA Repair, DNA Mutational Analysis, Carcinoma, Pancreatic Ductal, Animals, Adenocarcinoma, Xenograft Model Antitumor Assays

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          Abstract

          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.

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          Author and article information

          Journal
          25719666
          10.1038/nature14169
          4523082

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