Hypermutation in pancreatic cancer

Jeremy L. Humphris, Ann Marie Patch, Katia Nones, Peter J. Bailey, Amber L. Johns, Skye McKay, David K. Chang, David K. Miller, Marina Pajic, Karin S. Kassahn, Michael C. J. Quinn, Timothy J. C. Bruxner, Angelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Andrew Stone, Peter J. Wilson & 67 others Matthew Anderson, J. Lynn Fink, Oliver Holmes, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Nick Waddell, Scott Wood, Ronald S. Mead, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J. Cowley, Marc D. Jones, Adnan M. Nagrial, Venessa T. Chin, Lorraine A. Chantrill, Amanda Mawson, Angela Chou, Christopher J. Scarlett, Andreia V. Pinho, Ilse Rooman, Marc Giry-Laterriere, Jaswinder S. Samra, James G. Kench, Neil D. Merrett, Christopher W. Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B. Jamieson, Colin J. McKay, C. Ross Carter, Euan J. Dickson, Janet S. Graham, Fraser Duthie, Karin Oien, Jane Hair, Jennifer P. Morton, Owen J. Sansom, Robert Grützmann, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Borislav Rusev, Vincenzo Corbo, Roberto Salvia, Ivana Cataldo, Giampaolo Tortora, Margaret A. Tempero, Australian Pancreatic Cancer Genome Initiative, Oliver Hofmann, James R. Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A. Musgrove, Anthony J. Gill, John V. Pearson, Sean M. Grimmond, Nicola Waddell, Andrew V. Biankin, Vincent Lam

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages68-74.e2
Number of pages9
JournalGastroenterology
Volume152
Issue number1
DOIs
Publication statusPublished - Jan 2017
Externally publishedYes

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Pancreatic Neoplasms
DNA Repair
Mutation
Immunotherapy
Patient Selection
Neoplasms
Clinical Trials
Genome
Therapeutics

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Humphris, J. L., Patch, A. M., Nones, K., Bailey, P. J., Johns, A. L., McKay, S., ... Biankin, A. V. (2017). Hypermutation in pancreatic cancer. Gastroenterology, 152(1), 68-74.e2. https://doi.org/10.1053/j.gastro.2016.09.060
Humphris, Jeremy L. ; Patch, Ann Marie ; Nones, Katia ; Bailey, Peter J. ; Johns, Amber L. ; McKay, Skye ; Chang, David K. ; Miller, David K. ; Pajic, Marina ; Kassahn, Karin S. ; Quinn, Michael C. J. ; Bruxner, Timothy J. C. ; Christ, Angelika N. ; Harliwong, Ivon ; Idrisoglu, Senel ; Manning, Suzanne ; Nourse, Craig ; Nourbakhsh, Ehsan ; Stone, Andrew ; Wilson, Peter J. ; Anderson, Matthew ; Fink, J. Lynn ; Holmes, Oliver ; Kazakoff, Stephen ; Leonard, Conrad ; Newell, Felicity ; Waddell, Nick ; Wood, Scott ; Mead, Ronald S. ; Xu, Qinying ; Wu, Jianmin ; Pinese, Mark ; Cowley, Mark J. ; Jones, Marc D. ; Nagrial, Adnan M. ; Chin, Venessa T. ; Chantrill, Lorraine A. ; Mawson, Amanda ; Chou, Angela ; Scarlett, Christopher J. ; Pinho, Andreia V. ; Rooman, Ilse ; Giry-Laterriere, Marc ; Samra, Jaswinder S. ; Kench, James G. ; Merrett, Neil D. ; Toon, Christopher W. ; Epari, Krishna ; Nguyen, Nam Q. ; Barbour, Andrew ; Zeps, Nikolajs ; Jamieson, Nigel B. ; McKay, Colin J. ; Carter, C. Ross ; Dickson, Euan J. ; Graham, Janet S. ; Duthie, Fraser ; Oien, Karin ; Hair, Jane ; Morton, Jennifer P. ; Sansom, Owen J. ; Grützmann, Robert ; Hruban, Ralph H. ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Wolfgang, Christopher L. ; Morgan, Richard A. ; Lawlor, Rita T. ; Rusev, Borislav ; Corbo, Vincenzo ; Salvia, Roberto ; Cataldo, Ivana ; Tortora, Giampaolo ; Tempero, Margaret A. ; Australian Pancreatic Cancer Genome Initiative ; Hofmann, Oliver ; Eshleman, James R. ; Pilarsky, Christian ; Scarpa, Aldo ; Musgrove, Elizabeth A. ; Gill, Anthony J. ; Pearson, John V. ; Grimmond, Sean M. ; Waddell, Nicola ; Biankin, Andrew V. / Hypermutation in pancreatic cancer. In: Gastroenterology. 2017 ; Vol. 152, No. 1. pp. 68-74.e2.
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Humphris, JL, Patch, AM, Nones, K, Bailey, PJ, Johns, AL, McKay, S, Chang, DK, Miller, DK, Pajic, M, Kassahn, KS, Quinn, MCJ, Bruxner, TJC, Christ, AN, Harliwong, I, Idrisoglu, S, Manning, S, Nourse, C, Nourbakhsh, E, Stone, A, Wilson, PJ, Anderson, M, Fink, JL, Holmes, O, Kazakoff, S, Leonard, C, Newell, F, Waddell, N, Wood, S, Mead, RS, Xu, Q, Wu, J, Pinese, M, Cowley, MJ, Jones, MD, Nagrial, AM, Chin, VT, Chantrill, LA, Mawson, A, Chou, A, Scarlett, CJ, Pinho, AV, Rooman, I, Giry-Laterriere, M, Samra, JS, Kench, JG, Merrett, ND, Toon, CW, Epari, K, Nguyen, NQ, Barbour, A, Zeps, N, Jamieson, NB, McKay, CJ, Carter, CR, Dickson, EJ, Graham, JS, Duthie, F, Oien, K, Hair, J, Morton, JP, Sansom, OJ, Grützmann, R, Hruban, RH, Maitra, A, Iacobuzio-Donahue, CA, Schulick, RD, Wolfgang, CL, Morgan, RA, Lawlor, RT, Rusev, B, Corbo, V, Salvia, R, Cataldo, I, Tortora, G, Tempero, MA, Australian Pancreatic Cancer Genome Initiative, Hofmann, O, Eshleman, JR, Pilarsky, C, Scarpa, A, Musgrove, EA, Gill, AJ, Pearson, JV, Grimmond, SM, Waddell, N & Biankin, AV 2017, 'Hypermutation in pancreatic cancer' Gastroenterology, vol. 152, no. 1, pp. 68-74.e2. https://doi.org/10.1053/j.gastro.2016.09.060

Hypermutation in pancreatic cancer. / Humphris, Jeremy L.; Patch, Ann Marie; Nones, Katia; Bailey, Peter J.; Johns, Amber L.; McKay, Skye; Chang, David K.; Miller, David K.; Pajic, Marina; Kassahn, Karin S.; Quinn, Michael C. J.; Bruxner, Timothy J. C.; Christ, Angelika N.; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Stone, Andrew; Wilson, Peter J.; Anderson, Matthew; Fink, J. Lynn; Holmes, Oliver; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Mead, Ronald S.; Xu, Qinying; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Jones, Marc D.; Nagrial, Adnan M.; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Chou, Angela; Scarlett, Christopher J.; Pinho, Andreia V.; Rooman, Ilse; Giry-Laterriere, Marc; Samra, Jaswinder S.; Kench, James G.; Merrett, Neil D.; Toon, Christopher W.; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Jamieson, Nigel B.; McKay, Colin J.; Carter, C. Ross; Dickson, Euan J.; Graham, Janet S.; Duthie, Fraser; Oien, Karin; Hair, Jane; Morton, Jennifer P.; Sansom, Owen J.; Grützmann, Robert; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Rusev, Borislav; Corbo, Vincenzo; Salvia, Roberto; Cataldo, Ivana; Tortora, Giampaolo; Tempero, Margaret A.; Australian Pancreatic Cancer Genome Initiative; Hofmann, Oliver; Eshleman, James R.; Pilarsky, Christian; Scarpa, Aldo; Musgrove, Elizabeth A.; Gill, Anthony J.; Pearson, John V.; Grimmond, Sean M.; Waddell, Nicola; Biankin, Andrew V.

In: Gastroenterology, Vol. 152, No. 1, 01.2017, p. 68-74.e2.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Hypermutation in pancreatic cancer

AU - Humphris,Jeremy L.

AU - Patch,Ann Marie

AU - Nones,Katia

AU - Bailey,Peter J.

AU - Johns,Amber L.

AU - McKay,Skye

AU - Chang,David K.

AU - Miller,David K.

AU - Pajic,Marina

AU - Kassahn,Karin S.

AU - Quinn,Michael C. J.

AU - Bruxner,Timothy J. C.

AU - Christ,Angelika N.

AU - Harliwong,Ivon

AU - Idrisoglu,Senel

AU - Manning,Suzanne

AU - Nourse,Craig

AU - Nourbakhsh,Ehsan

AU - Stone,Andrew

AU - Wilson,Peter J.

AU - Anderson,Matthew

AU - Fink,J. Lynn

AU - Holmes,Oliver

AU - Kazakoff,Stephen

AU - Leonard,Conrad

AU - Newell,Felicity

AU - Waddell,Nick

AU - Wood,Scott

AU - Mead,Ronald S.

AU - Xu,Qinying

AU - Wu,Jianmin

AU - Pinese,Mark

AU - Cowley,Mark J.

AU - Jones,Marc D.

AU - Nagrial,Adnan M.

AU - Chin,Venessa T.

AU - Chantrill,Lorraine A.

AU - Mawson,Amanda

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AU - Scarlett,Christopher J.

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AU - Merrett,Neil D.

AU - Toon,Christopher W.

AU - Epari,Krishna

AU - Nguyen,Nam Q.

AU - Barbour,Andrew

AU - Zeps,Nikolajs

AU - Jamieson,Nigel B.

AU - McKay,Colin J.

AU - Carter,C. Ross

AU - Dickson,Euan J.

AU - Graham,Janet S.

AU - Duthie,Fraser

AU - Oien,Karin

AU - Hair,Jane

AU - Morton,Jennifer P.

AU - Sansom,Owen J.

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AU - Hruban,Ralph H.

AU - Maitra,Anirban

AU - Iacobuzio-Donahue,Christine A.

AU - Schulick,Richard D.

AU - Wolfgang,Christopher L.

AU - Morgan,Richard A.

AU - Lawlor,Rita T.

AU - Rusev,Borislav

AU - Corbo,Vincenzo

AU - Salvia,Roberto

AU - Cataldo,Ivana

AU - Tortora,Giampaolo

AU - Tempero,Margaret A.

AU - Australian Pancreatic Cancer Genome Initiative

AU - Hofmann,Oliver

AU - Eshleman,James R.

AU - Pilarsky,Christian

AU - Scarpa,Aldo

AU - Musgrove,Elizabeth A.

AU - Gill,Anthony J.

AU - Pearson,John V.

AU - Grimmond,Sean M.

AU - Waddell,Nicola

AU - Biankin,Andrew V.

AU - Lam,Vincent

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Y1 - 2017/1

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AB - 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.

KW - pancreatic adenocarcinoma

KW - sequencing

KW - somatic rearrangement

KW - cancer genetics

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UR - http://purl.org/au-research/grants/nhmrc/631701

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DO - 10.1053/j.gastro.2016.09.060

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JF - Gastroenterology

SN - 0016-5085

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Humphris JL, Patch AM, Nones K, Bailey PJ, Johns AL, McKay S et al. Hypermutation in pancreatic cancer. Gastroenterology. 2017 Jan;152(1):68-74.e2. https://doi.org/10.1053/j.gastro.2016.09.060