Whole genomes redefine the mutational landscape of pancreatic cancer
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Article
Nature volume 518, pages 495–501 (26 February 2015) | Download Citation
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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BAM files and associated metadata in XML format have been uploaded to the European Genome-phenome Archive (EGA; http://www.ebi.ac.uk/ega) under accession number EGAS00001000154. All SNP array data is available via GEO (GSE61502). For more information about Australian Pancreatic Cancer Genome Initiative, see (http://www.pancreaticcancer.net.au/apgi/collaborators).
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We would like to thank C. Axford, M.-A. Brancato, S. Rowe, M. Thomas, S. Simpson and G. Hammond for central coordination of the Australian Pancreatic Cancer Genome Initiative, data management and quality control; M. Martyn-Smith, L. Braatvedt, H. Tang, V. Papangelis and M. Beilin for biospecimen acquisition; and D. Gwynne for support at the Queensland Centre for Medical Genomics. We also thank M. Hodgins, M. Debeljak and D. Trusty for technical assistance at Johns Hopkins University. N. Sperandio and D. Filippini for technical assistance at Verona University. We acknowledge the following funding support: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601); Queensland Government (NIRAP); University of Queensland; Institute for Molecular Bioscience; Cancer Research UK (C596/A18076, C29717/A17263); Australian Government: Department of Innovation, Industry, Science and Research (DIISR); Australian Cancer Research Foundation (ACRF); Cancer Council NSW: (SRP06-01, SRP11-01. ICGC); Cancer Institute NSW: (10/ECF/2-26; 06/ECF/1-24; 09/CDF/2-40; 07/CDF/1-03; 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Research Foundation; University of Glasgow; Cancer Research UK; Howat Foundation; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation – INNOVATOR Award; Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); Italian Ministry of Research (Cancer Genome Project FIRB RBAP10AHJB); Associazione Italiana Ricerca Cancro (12182); Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001); Wilhelm Sander Stiftung 2009.039.2; National Institutes of Health grant P50 CA62924.
These authors jointly supervised this work.
Deceased.
(Participants are arranged by institution.)
Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the Queensland Centre for Medical Genomics. Investigator contributions are as follows: A.V.B. and S.M.G. (concept and design); S.M.G., J.V.P. N.W., A.V.B. (project leaders); N.W., S.M.G., D.K.C., A.V.B. (writing team); J.V.P., S.M.G., N.W., A.L.J., P.B., S.S., K.S.K., Nk.W., P.J.W., A.M.P., F.N., B.P., E.M., O.H., J.L.F., C.L., D.T., S.W., Q.X., K.N., N.C., M.C.J.Q., M.J.A., M.Z.H.F., A.J.R., S.K., K.Q., M.Pi., H.C.L., M.J.C. and J.W. (bioinformatics); M.Pa., C.J.S., D.K.C., E.S.H., A.M.N., A.C., A.S., C.S., A.V.P., I.R., A.M.S., S.P.N., R. B. (preclinical testing); A.L.J., M.D.J., M.P., C.J.S., C.T., A.M.N., V.T.C., L.A.C., J.S.S., D.K.C., V.C., A.S., C.S., A.J.G., J.A.L., I.R., A.V.P., E.A.M. (sample processing and quality control); A.J.G., J.G.K., C.T., G.Z., A.S., D.A. R.H.H., A.M., C.A.I-D., A.S. (pathology assessment); A.L.J., L.A.C., A.J.G., A.C., R.S.M., C.B., M.F., G.T., J.S.S., J.G.K., C.T., K.E., N.Q.N., N.Z., H.W., N.B.J., J.S.G, R.G., C.P., R.G., C.L.W., R.A.M., R.T.L., M.F., G.Z., G.T., M.A.T., A.P.G.I., J.R.E., R.H.H., A.M., C.A.I-D., A.S. (sample collection and clinical annotation); D.M., T.J.C.B., A.N.C., I.H., S.I., S.M., C.N., E.N., S.W. (sequencing). All authors have read and approved the final manuscript.
The authors declare no competing financial interests.
Correspondence to Sean M. Grimmond or Sean M. Grimmond.
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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.
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Whole genomes redefine the mutational landscape of pancreatic cancer
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