Whole genomes redefine the mutational landscape of pancreatic cancer

Waddell, N. et al. (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518(7540), pp. 495-501. (doi:10.1038/nature14169) (PMID:25719666) (PMCID:PMC4523082)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jones, Mr Marc and Jamieson, Dr Nigel and Bailey, Dr Peter and Oien, Dr Karin and Biankin, Professor Andrew and Musgrove, Dr Elizabeth and Grimmond, Professor Sean and Nourse, Dr Craig and Chang, Dr David and Graham, Dr Janet
Authors: Waddell, N., 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., Biankin, A. V., Johns, A. L., Mawson, A., Chang, D. K., Scarlett, C. J., Brancato, M.-A. L., Rowe, S. J., Simpson, S. H., Martyn-Smith, M., Thomas, M. T., Chantrill, L. A., Chin, V. T., Chou, A., Cowley, M. J., Humphris, J. L., Jones, M. D., Scott Mead, R., Nagrial, A. M., Pajic, M., Pettit, J., Pinese, M., Rooman, I., Wu, J., Tao, J., DiPietro, R., Watson, C., Steinmann, A., Ching Lee, H., Wong, R., Pinho, A. V., Giry-Laterriere, M., Daly, R. J., Musgrove, E. A., Sutherland, R. L., Grimmond, S. M., Waddell, N., Kassahn, K. S., Miller, D. K., Wilson, P. J., Patch, A.-M., Song, S., Harliwong, I., Idrisoglu, S., Nourse, C., Nourbakhsh, E., Manning, S., Wani, S., Gongora, M., Anderson, M., Holmes, O., Leonard, C., Taylor, D., Wood, S., Xu, C., Nones, K., Lynn Fink, J., Christ, A., Bruxner, T., Cloonan, N., Newell, F., Pearson, J. V., Bailey, P., Quinn, M., Nagaraj, S., Kazakoff, S., Waddell, N., Krisnan, K., Quek, K., Wood, D., Fadlullah, M. Z. H., Samra, J. S., Gill, A. J., Pavlakis, N., Guminski, A., Toon, C., Asghari, R., Merrett, N. D., Pavey, D., Das, A., Cosman, P. H., Ismail, K., O’Connnor, C., Lam Duncan McLeod, V. W., Pleass, H. C., Richardson, A., James, V., Kench, J. G., Cooper, C. L., Joseph, D., Sandroussi, C., Crawford, M., Gallagher, J., Texler, M., Forest, C., Laycock, A., Epari, K. P., Ballal, M., Fletcher, D. R., Mukhedkar, S., Spry, N. A., DeBoer, B., Chai, M., Zeps, N., Beilin, M., Feeney, K., Nguyen, N. Q., Ruszkiewicz, A. R., Worthley, C., Tan, C. P., Debrencini, T., Chen, J., Brooke-Smith, M. E., Papangelis, V., Tang, H., Barbour, A. P., Clouston, A. D., Martin, P., O’Rourke, T. J., Chiang, A., Fawcett, J. W., Slater, K., Yeung, S., Hatzifotis, M., Hodgkinson, P., Christophi, C., Nikfarjam, M., Mountain, A., Eshleman, J. R., Hruban, R. H., Maitra, A., Iacobuzio-Donahue, C. A., Schulick, R. D., Wolfgang, C. L., Morgan, R. A., Hodgin, M., Scarpa, A., Lawlor, R. T., Beghelli, S., Corbo, V., Scardoni, M., Bassi, C., Tempero, M. A., Biankin, A. V., Grimmond, S. M., Chang, D. K., Musgrove, E. A., Jones, M. D., Nourse, C., Jamieson, N. B., Graham, J. S., Biankin, A. V., Chang, D. K., Jamieson, N. B., Graham, J. S., Oien, K., Hair, J., Gill, A. J., Eshleman, J. R., Pilarsky, C., Scarpa, A., Musgrove, E. A., Pearson, J. V., Biankin, A. V., and Grimmond, S. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Related URLs:

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)C596/A18076RI CANCER SCIENCES
645511Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CAN-RES-UK)C29717/A17263ICS - TRANSLATIONAL RESEARCH CENTRE
698991Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CAN-RES-UK)C29717/A17263ICS - TRANSLATIONAL RESEARCH CENTRE