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Hypermutation in pancreatic cancer

Abstract

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

Type Journal
ISBN 1528-0012 (Electronic) 0016-5085 (Linking)
Authors Humphris, J. L.; Patch, A. M.; Nones, K.; Bailey, P. J.; Johns, A. L.; McKay, S.; Chang, D. K.; Miller, D. K.; Pajic, M.; Kassahn, K. S.; Quinn, M. C.; Bruxner, T. J.; Christ, A. N.; Harliwong, I.; Idrisoglu, S.; Manning, S.; Nourse, C.; Nourbakhsh, E.; Stone, A.; Wilson, P. J.; Anderson, M.; Fink, J. L.; Holmes, O.; Kazakoff, S.; Leonard, C.; Newell, F.; Waddell, N.; Wood, S.; Mead, R. S.; Xu, Q.; Wu, J.; Pinese, M.; Cowley, M. J.; Jones, M. D.; Nagrial, A. M.; Chin, V. T.; Chantrill, L. A.; Mawson, A.; Chou, A.; Scarlett, C. J.; Pinho, A. V.; Rooman, I.; Giry-Laterriere, M.; Samra, J. S.; Kench, J. G.; Merrett, N. D.; Toon, C. W.; Epari, K.; Nguyen, N. Q.; Barbour, A.; Zeps, N.; Jamieson, N. B.; McKay, C. J.; Carter, C. R.; Dickson, E. J.; Graham, J. S.; Duthie, F.; Oien, K.; Hair, J.; Morton, J. P.; Sansom, O. J.; Grutzmann, R.; Hruban, R. H.; Maitra, A.; Iacobuzio-Donahue, C. A.; Schulick, R. D.; Wolfgang, C. L.; Morgan, R. A.; Lawlor, R. T.; Rusev, B.; Corbo, V.; Salvia, R.; Cataldo, I.; Tortora, G.; Tempero, M. A.; Australian Pancreatic Cancer Genome Initiative, .; Hofmann, O.; Eshleman, J. R.; Pilarsky, C.; Scarpa, A.; Musgrove, E. A.; Gill, A. J.; Pearson, J. V.; Grimmond, S. M.; Waddell, N.; Biankin, A. V.
Responsible Garvan Author Dr Marina Pajic
Publisher Name GASTROENTEROLOGY
Published Date 2017-01-31
Published Volume 152
Published Issue 1
Published Pages 68-74 e2
Status Published in-print
DOI 10.1053/j.gastro.2016.09.060
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/27856273
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14254