Genomic analyses identify molecular subtypes of pancreatic cancer

Peter Bailey, David K. Chang, Katia Nones, Amber L. Johns, Ann Marie Patch, Marie Claude Gingras, David K. Miller, Angelika N. Christ, Tim J C Bruxner, Michael C. Quinn, Craig Nourse, L. Charles Murtaugh, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Ehsan Nourbakhsh, Shivangi Wani, Lynn Fink, Oliver Holmes, Venessa Chin & 84 others Matthew J. Anderson, Stephen Kazakoff, Conrad Leonard, Felicity Newell, Nick Waddell, Scott Wood, Qinying Xu, Peter J. Wilson, Nicole Cloonan, Karin S. Kassahn, Darrin Taylor, Kelly Quek, Alan Robertson, Lorena Pantano, Laura Mincarelli, Luis N. Sanchez, Lisa Evers, Jianmin Wu, Mark Pinese, Mark J. Cowley, Marc D. Jones, Emily K. Colvin, Adnan M. Nagrial, Emily S. Humphrey, Lorraine A. Chantrill, Amanda Mawson, Jeremy Humphris, Angela Chou, Marina Pajic, Christopher J. Scarlett, Andreia V. Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S. Samra, James G. Kench, Jessica A. Lovell, Neil D. Merrett, Christopher W. Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Kim Moran-Jones, Nigel B. Jamieson, Janet S. Graham, Fraser Duthie, Karin Oien, Jane Hair, Robert Grützmann, Anirban Maitra, Christine A. Iacobuzio-Donahue, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Vincenzo Corbo, Claudio Bassi, Borislav Rusev, Paola Capelli, Roberto Salvia, Giampaolo Tortora, Debabrata Mukhopadhyay, Gloria M. Petersen, Donna M. Munzy, William E. Fisher, Saadia A. Karim, James R. Eshleman, Ralph H. Hruban, Christian Pilarsky, Jennifer P. Morton, Owen J. Sansom, Aldo Scarpa, Elizabeth A. Musgrove, Ulla Maja Hagbo Bailey, Oliver Hofmann, Robert L. Sutherland, David A. Wheeler, Anthony J. Gill, Richard A. Gibbs, John V. Pearson, Nicola Waddell, Andrew V. Biankin, Sean M. Grimmond, Australian Pancreatic Cancer Genome Initiative, Vincent Lam

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

LanguageEnglish
Pages47-52
Number of pages6
JournalNature
Volume531
Issue number7592
DOIs
Publication statusPublished - 3 Mar 2016
Externally publishedYes

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Pancreatic Neoplasms
Gene Regulatory Networks
Neoplasms
Up-Regulation
Genes
Molecular Evolution
DNA Repair
Transforming Growth Factor beta
Chromatin
Adenocarcinoma
RNA
Mutation
Therapeutics

Cite this

Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. M., Gingras, M. C., ... Australian Pancreatic Cancer Genome Initiative (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531(7592), 47-52. https://doi.org/10.1038/nature16965
Bailey, Peter ; Chang, David K. ; Nones, Katia ; Johns, Amber L. ; Patch, Ann Marie ; Gingras, Marie Claude ; Miller, David K. ; Christ, Angelika N. ; Bruxner, Tim J C ; Quinn, Michael C. ; Nourse, Craig ; Murtaugh, L. Charles ; Harliwong, Ivon ; Idrisoglu, Senel ; Manning, Suzanne ; Nourbakhsh, Ehsan ; Wani, Shivangi ; Fink, Lynn ; Holmes, Oliver ; Chin, Venessa ; Anderson, Matthew J. ; Kazakoff, Stephen ; Leonard, Conrad ; Newell, Felicity ; Waddell, Nick ; Wood, Scott ; Xu, Qinying ; Wilson, Peter J. ; Cloonan, Nicole ; Kassahn, Karin S. ; Taylor, Darrin ; Quek, Kelly ; Robertson, Alan ; Pantano, Lorena ; Mincarelli, Laura ; Sanchez, Luis N. ; Evers, Lisa ; Wu, Jianmin ; Pinese, Mark ; Cowley, Mark J. ; Jones, Marc D. ; Colvin, Emily K. ; Nagrial, Adnan M. ; Humphrey, Emily S. ; Chantrill, Lorraine A. ; Mawson, Amanda ; Humphris, Jeremy ; Chou, Angela ; Pajic, Marina ; Scarlett, Christopher J. ; Pinho, Andreia V. ; Giry-Laterriere, Marc ; Rooman, Ilse ; Samra, Jaswinder S. ; Kench, James G. ; Lovell, Jessica A. ; Merrett, Neil D. ; Toon, Christopher W. ; Epari, Krishna ; Nguyen, Nam Q. ; Barbour, Andrew ; Zeps, Nikolajs ; Moran-Jones, Kim ; Jamieson, Nigel B. ; Graham, Janet S. ; Duthie, Fraser ; Oien, Karin ; Hair, Jane ; Grützmann, Robert ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Wolfgang, Christopher L. ; Morgan, Richard A. ; Lawlor, Rita T. ; Corbo, Vincenzo ; Bassi, Claudio ; Rusev, Borislav ; Capelli, Paola ; Salvia, Roberto ; Tortora, Giampaolo ; Mukhopadhyay, Debabrata ; Petersen, Gloria M. ; Munzy, Donna M. ; Fisher, William E. ; Karim, Saadia A. ; Eshleman, James R. ; Hruban, Ralph H. ; Pilarsky, Christian ; Morton, Jennifer P. ; Sansom, Owen J. ; Scarpa, Aldo ; Musgrove, Elizabeth A. ; Bailey, Ulla Maja Hagbo ; Hofmann, Oliver ; Sutherland, Robert L. ; Wheeler, David A. ; Gill, Anthony J. ; Gibbs, Richard A. ; Pearson, John V. ; Waddell, Nicola ; Biankin, Andrew V. ; Grimmond, Sean M. ; Australian Pancreatic Cancer Genome Initiative. / Genomic analyses identify molecular subtypes of pancreatic cancer. In: Nature. 2016 ; Vol. 531, No. 7592. pp. 47-52.
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title = "Genomic analyses identify molecular subtypes of pancreatic cancer",
abstract = "Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.",
author = "Peter Bailey and Chang, {David K.} and Katia Nones and Johns, {Amber L.} and Patch, {Ann Marie} and Gingras, {Marie Claude} and Miller, {David K.} and Christ, {Angelika N.} and Bruxner, {Tim J C} and Quinn, {Michael C.} and Craig Nourse and Murtaugh, {L. Charles} and Ivon Harliwong and Senel Idrisoglu and Suzanne Manning and Ehsan Nourbakhsh and Shivangi Wani and Lynn Fink and Oliver Holmes and Venessa Chin and Anderson, {Matthew J.} and Stephen Kazakoff and Conrad Leonard and Felicity Newell and Nick Waddell and Scott Wood and Qinying Xu and Wilson, {Peter J.} and Nicole Cloonan and Kassahn, {Karin S.} and Darrin Taylor and Kelly Quek and Alan Robertson and Lorena Pantano and Laura Mincarelli and Sanchez, {Luis N.} and Lisa Evers and Jianmin Wu and Mark Pinese and Cowley, {Mark J.} and Jones, {Marc D.} and Colvin, {Emily K.} and Nagrial, {Adnan M.} and Humphrey, {Emily S.} and Chantrill, {Lorraine A.} and Amanda Mawson and Jeremy Humphris and Angela Chou and Marina Pajic and Scarlett, {Christopher J.} and Pinho, {Andreia V.} and Marc Giry-Laterriere and Ilse Rooman and Samra, {Jaswinder S.} and Kench, {James G.} and Lovell, {Jessica A.} and Merrett, {Neil D.} and Toon, {Christopher W.} and Krishna Epari and Nguyen, {Nam Q.} and Andrew Barbour and Nikolajs Zeps and Kim Moran-Jones and Jamieson, {Nigel B.} and Graham, {Janet S.} and Fraser Duthie and Karin Oien and Jane Hair and Robert Gr{\"u}tzmann and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Lawlor, {Rita T.} and Vincenzo Corbo and Claudio Bassi and Borislav Rusev and Paola Capelli and Roberto Salvia and Giampaolo Tortora and Debabrata Mukhopadhyay and Petersen, {Gloria M.} and Munzy, {Donna M.} and Fisher, {William E.} and Karim, {Saadia A.} and Eshleman, {James R.} and Hruban, {Ralph H.} and Christian Pilarsky and Morton, {Jennifer P.} and Sansom, {Owen J.} and Aldo Scarpa and Musgrove, {Elizabeth A.} and Bailey, {Ulla Maja Hagbo} and Oliver Hofmann and Sutherland, {Robert L.} and Wheeler, {David A.} and Gill, {Anthony J.} and Gibbs, {Richard A.} and Pearson, {John V.} and Nicola Waddell and Biankin, {Andrew V.} and Grimmond, {Sean M.} and {Australian Pancreatic Cancer Genome Initiative} and Vincent Lam",
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Bailey, P, Chang, DK, Nones, K, Johns, AL, Patch, AM, Gingras, MC, Miller, DK, Christ, AN, Bruxner, TJC, Quinn, MC, Nourse, C, Murtaugh, LC, Harliwong, I, Idrisoglu, S, Manning, S, Nourbakhsh, E, Wani, S, Fink, L, Holmes, O, Chin, V, Anderson, MJ, Kazakoff, S, Leonard, C, Newell, F, Waddell, N, Wood, S, Xu, Q, Wilson, PJ, Cloonan, N, Kassahn, KS, Taylor, D, Quek, K, Robertson, A, Pantano, L, Mincarelli, L, Sanchez, LN, Evers, L, Wu, J, Pinese, M, Cowley, MJ, Jones, MD, Colvin, EK, Nagrial, AM, Humphrey, ES, Chantrill, LA, Mawson, A, Humphris, J, Chou, A, Pajic, M, Scarlett, CJ, Pinho, AV, Giry-Laterriere, M, Rooman, I, Samra, JS, Kench, JG, Lovell, JA, Merrett, ND, Toon, CW, Epari, K, Nguyen, NQ, Barbour, A, Zeps, N, Moran-Jones, K, Jamieson, NB, Graham, JS, Duthie, F, Oien, K, Hair, J, Grützmann, R, Maitra, A, Iacobuzio-Donahue, CA, Wolfgang, CL, Morgan, RA, Lawlor, RT, Corbo, V, Bassi, C, Rusev, B, Capelli, P, Salvia, R, Tortora, G, Mukhopadhyay, D, Petersen, GM, Munzy, DM, Fisher, WE, Karim, SA, Eshleman, JR, Hruban, RH, Pilarsky, C, Morton, JP, Sansom, OJ, Scarpa, A, Musgrove, EA, Bailey, UMH, Hofmann, O, Sutherland, RL, Wheeler, DA, Gill, AJ, Gibbs, RA, Pearson, JV, Waddell, N, Biankin, AV, Grimmond, SM & Australian Pancreatic Cancer Genome Initiative 2016, 'Genomic analyses identify molecular subtypes of pancreatic cancer', Nature, vol. 531, no. 7592, pp. 47-52. https://doi.org/10.1038/nature16965

Genomic analyses identify molecular subtypes of pancreatic cancer. / Bailey, Peter; Chang, David K.; Nones, Katia; Johns, Amber L.; Patch, Ann Marie; Gingras, Marie Claude; Miller, David K.; Christ, Angelika N.; Bruxner, Tim J C; Quinn, Michael C.; Nourse, Craig; Murtaugh, L. Charles; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourbakhsh, Ehsan; Wani, Shivangi; Fink, Lynn; Holmes, Oliver; Chin, Venessa; Anderson, Matthew J.; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Xu, Qinying; Wilson, Peter J.; Cloonan, Nicole; Kassahn, Karin S.; Taylor, Darrin; Quek, Kelly; Robertson, Alan; Pantano, Lorena; Mincarelli, Laura; Sanchez, Luis N.; Evers, Lisa; Wu, Jianmin; Pinese, Mark; Cowley, Mark J.; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chantrill, Lorraine A.; Mawson, Amanda; Humphris, Jeremy; Chou, Angela; Pajic, Marina; Scarlett, Christopher J.; Pinho, Andreia V.; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Merrett, Neil D.; Toon, Christopher W.; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Moran-Jones, Kim; Jamieson, Nigel B.; Graham, Janet S.; Duthie, Fraser; Oien, Karin; Hair, Jane; Grützmann, Robert; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Corbo, Vincenzo; Bassi, Claudio; Rusev, Borislav; Capelli, Paola; Salvia, Roberto; Tortora, Giampaolo; Mukhopadhyay, Debabrata; Petersen, Gloria M.; Munzy, Donna M.; Fisher, William E.; Karim, Saadia A.; Eshleman, James R.; Hruban, Ralph H.; Pilarsky, Christian; Morton, Jennifer P.; Sansom, Owen J.; Scarpa, Aldo; Musgrove, Elizabeth A.; Bailey, Ulla Maja Hagbo; Hofmann, Oliver; Sutherland, Robert L.; Wheeler, David A.; Gill, Anthony J.; Gibbs, Richard A.; Pearson, John V.; Waddell, Nicola; Biankin, Andrew V.; Grimmond, Sean M.; Australian Pancreatic Cancer Genome Initiative.

In: Nature, Vol. 531, No. 7592, 03.03.2016, p. 47-52.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genomic analyses identify molecular subtypes of pancreatic cancer

AU - Bailey, Peter

AU - Chang, David K.

AU - Nones, Katia

AU - Johns, Amber L.

AU - Patch, Ann Marie

AU - Gingras, Marie Claude

AU - Miller, David K.

AU - Christ, Angelika N.

AU - Bruxner, Tim J C

AU - Quinn, Michael C.

AU - Nourse, Craig

AU - Murtaugh, L. Charles

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Manning, Suzanne

AU - Nourbakhsh, Ehsan

AU - Wani, Shivangi

AU - Fink, Lynn

AU - Holmes, Oliver

AU - Chin, Venessa

AU - Anderson, Matthew J.

AU - Kazakoff, Stephen

AU - Leonard, Conrad

AU - Newell, Felicity

AU - Waddell, Nick

AU - Wood, Scott

AU - Xu, Qinying

AU - Wilson, Peter J.

AU - Cloonan, Nicole

AU - Kassahn, Karin S.

AU - Taylor, Darrin

AU - Quek, Kelly

AU - Robertson, Alan

AU - Pantano, Lorena

AU - Mincarelli, Laura

AU - Sanchez, Luis N.

AU - Evers, Lisa

AU - Wu, Jianmin

AU - Pinese, Mark

AU - Cowley, Mark J.

AU - Jones, Marc D.

AU - Colvin, Emily K.

AU - Nagrial, Adnan M.

AU - Humphrey, Emily S.

AU - Chantrill, Lorraine A.

AU - Mawson, Amanda

AU - Humphris, Jeremy

AU - Chou, Angela

AU - Pajic, Marina

AU - Scarlett, Christopher J.

AU - Pinho, Andreia V.

AU - Giry-Laterriere, Marc

AU - Rooman, Ilse

AU - Samra, Jaswinder S.

AU - Kench, James G.

AU - Lovell, Jessica A.

AU - Merrett, Neil D.

AU - Toon, Christopher W.

AU - Epari, Krishna

AU - Nguyen, Nam Q.

AU - Barbour, Andrew

AU - Zeps, Nikolajs

AU - Moran-Jones, Kim

AU - Jamieson, Nigel B.

AU - Graham, Janet S.

AU - Duthie, Fraser

AU - Oien, Karin

AU - Hair, Jane

AU - Grützmann, Robert

AU - Maitra, Anirban

AU - Iacobuzio-Donahue, Christine A.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Lawlor, Rita T.

AU - Corbo, Vincenzo

AU - Bassi, Claudio

AU - Rusev, Borislav

AU - Capelli, Paola

AU - Salvia, Roberto

AU - Tortora, Giampaolo

AU - Mukhopadhyay, Debabrata

AU - Petersen, Gloria M.

AU - Munzy, Donna M.

AU - Fisher, William E.

AU - Karim, Saadia A.

AU - Eshleman, James R.

AU - Hruban, Ralph H.

AU - Pilarsky, Christian

AU - Morton, Jennifer P.

AU - Sansom, Owen J.

AU - Scarpa, Aldo

AU - Musgrove, Elizabeth A.

AU - Bailey, Ulla Maja Hagbo

AU - Hofmann, Oliver

AU - Sutherland, Robert L.

AU - Wheeler, David A.

AU - Gill, Anthony J.

AU - Gibbs, Richard A.

AU - Pearson, John V.

AU - Waddell, Nicola

AU - Biankin, Andrew V.

AU - Grimmond, Sean M.

AU - Australian Pancreatic Cancer Genome Initiative

AU - Lam, Vincent

PY - 2016/3/3

Y1 - 2016/3/3

N2 - Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

AB - Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

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Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016 Mar 3;531(7592):47-52. https://doi.org/10.1038/nature16965