Whole genomes redefine the mutational landscape of pancreatic cancer Journal Article
| Authors: | Pajic, M.; Patch, A. M.; Chang, D. K.; Kassahn, K. S.; Bailey, P.; Johns, A. L.; Miller, D.; Nones, K.; Quek, K.; Quinn, M. C. J.; Robertson, A. J.; Fadlullah, M. Z. H.; Bruxner, T. J. C.; Christ, A. N.; Harliwong, I.; Idrisoglu, S.; Manning, S.; Nourse, C.; Nourbakhsh, E.; Wani, S.; Wilson, P. J.; Markham, E.; Cloonan, N.; Anderson, M. J.; Fink, J. L.; Holmes, O.; Kazakoff, S. H.; Leonard, C.; Newell, F.; Poudel, B.; Song, S.; Taylor, D.; Waddell, N.; Wood, S.; Xu, Q.; Wu, J.; Pinese, M.; Cowley, M. J.; Lee, H. C.; Jones, M. D.; Nagrial, A. M.; Humphris, J.; Chantrill, L. A.; Chin, V.; Steinmann, A. M.; Mawson, A.; Humphrey, E. S.; Colvin, E. K.; Chou, A.; Scarlett, C. J.; Pinho, A. V.; Giry-Laterriere, M.; Rooman, I.; Samra, J. S.; Kench, J. G.; Pettitt, J. A.; Merrett, N. D.; Toon, C.; Epari, K.; Nguyen, N. Q.; Barbour, A.; Zeps, N.; Jamieson, N. B.; Graham, J. S.; Niclou, S. P.; Bjerkvig, R.; Grützmann, R.; Aust, D.; Hruban, R. H.; Maitra, A.; Iacobuzio-Donahue, C. A.; Wolfgang, C. L.; Morgan, R. A.; Lawlor, R. T.; Corbo, V.; Bassi, C.; Falconi, M.; Zamboni, G.; Tortora, G.; Tempero, M. A.; Gill, A. J.; Eshleman, J. R.; Pilarsky, C.; Scarpa, A.; Musgrove, E. A.; Pearson, J. V.; Biankin, A. V.; Grimmond, S. M. |
| Article Title: | Whole genomes redefine the mutational landscape of pancreatic cancer |
| 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. © 2015 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | cancer chemotherapy; unclassified drug; gene mutation; somatic mutation; mutation; cancer patient; pancreas cancer; antineoplastic agent; dna repair; prevalence; epidermal growth factor receptor 2; protein; genetic variability; brca1 protein; brca2 protein; protein p53; carcinogenesis; genetic engineering; gene disruption; genomic instability; pancreas adenocarcinoma; chromosome rearrangement; genome; cyclin dependent kinase inhibitor 2a; point mutation; fibroblast growth factor receptor 1; scatter factor receptor; cyclin dependent kinase 6; transcription factor gata 6; copy number variation; guanine nucleotide exchange factor; smad4 protein; palb2 protein; retinoblastoma binding protein 2; kdm6a protein; cancer; human; priority journal; article; pik3r3 protein; robo2 protein |
| Journal Title: | Nature |
| Volume: | 518 |
| Issue: | 7540 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-02-26 |
| Start Page: | 495 |
| End Page: | 501 |
| Language: | English |
| DOI: | 10.1038/nature14169 |
| PROVIDER: | scopus |
| PUBMED: | 25719666 |
| PMCID: | PMC4523082 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
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