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; 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

doi:10.1038/nature16965

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 ChinMatthew 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

Risultato della ricerca: Contributo in rivista › Articolo in rivista

1336 Citazioni (Scopus)

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.

Lingua originale	English
pagine (da-a)	47-52
Numero di pagine	6
Rivista	Nature
Volume	531
DOI	https://doi.org/10.1038/nature16965
Stato di pubblicazione	Pubblicato - 2016

Keywords

Animals
Basic Helix-Loop-Helix Transcription Factors
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
DNA Methylation
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
Genes, Neoplasm
Genome, Human
Genomics
Hepatocyte Nuclear Factor 3-beta
Hepatocyte Nuclear Factor 3-gamma
Histone Demethylases
Homeodomain Proteins
Humans
Mice
Mutation
Nuclear Proteins
Pancreatic Neoplasms
Prognosis
Receptors, Cytoplasmic and Nuclear
Survival Analysis
Trans-Activators
Transcription Factors
Transcription, Genetic
Transcriptome
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Zebrafish Proteins

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10.1038/nature16965

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Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., Nourse, C., Murtaugh, L. C., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., ... Grimmond, S. M. (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531, 47-52. https://doi.org/10.1038/nature16965

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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.",

keywords = "Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, DNA Methylation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genes, Neoplasm, Genome, Human, Genomics, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 3-gamma, Histone Demethylases, Homeodomain Proteins, Humans, Mice, Mutation, Nuclear Proteins, Pancreatic Neoplasms, Prognosis, Receptors, Cytoplasmic and Nuclear, Survival Analysis, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptome, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Zebrafish Proteins, Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, DNA Methylation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genes, Neoplasm, Genome, Human, Genomics, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 3-gamma, Histone Demethylases, Homeodomain Proteins, Humans, Mice, Mutation, Nuclear Proteins, Pancreatic Neoplasms, Prognosis, Receptors, Cytoplasmic and Nuclear, Survival Analysis, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptome, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Zebrafish Proteins",

author = "Peter Bailey and Chang, {David K.} and Katia Nones and Johns, {Amber L.} and Ann-Marie Patch and Marie-Claude Gingras 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.}",

year = "2016",

doi = "10.1038/nature16965",

language = "English",

volume = "531",

pages = "47--52",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

}

Bailey, P, Chang, DK, Nones, K, Johns, AL, Patch, A-M, Gingras, M-C, 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, U-MH, Hofmann, O, Sutherland, RL, Wheeler, DA, Gill, AJ, Gibbs, RA, Pearson, JV, Waddell, N, Biankin, AV & Grimmond, SM 2016, 'Genomic analyses identify molecular subtypes of pancreatic cancer', Nature, vol. 531, pagg. 47-52. https://doi.org/10.1038/nature16965

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.

PY - 2016

Y1 - 2016

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.

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Carcinoma, Pancreatic Ductal

KW - Cell Line, Tumor

KW - DNA Methylation

KW - DNA-Binding Proteins

KW - Gene Expression Regulation, Neoplastic

KW - Gene Regulatory Networks

KW - Genes, Neoplasm

KW - Genome, Human

KW - Genomics

KW - Hepatocyte Nuclear Factor 3-beta

KW - Hepatocyte Nuclear Factor 3-gamma

KW - Histone Demethylases

KW - Homeodomain Proteins

KW - Humans

KW - Mice

KW - Mutation

KW - Nuclear Proteins

KW - Pancreatic Neoplasms

KW - Prognosis

KW - Receptors, Cytoplasmic and Nuclear

KW - Survival Analysis

KW - Trans-Activators

KW - Transcription Factors

KW - Transcription, Genetic

KW - Transcriptome

KW - Tumor Suppressor Protein p53

KW - Tumor Suppressor Proteins

KW - Zebrafish Proteins

KW - Animals

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Carcinoma, Pancreatic Ductal

KW - Cell Line, Tumor

KW - DNA Methylation

KW - DNA-Binding Proteins

KW - Gene Expression Regulation, Neoplastic

KW - Gene Regulatory Networks

KW - Genes, Neoplasm

KW - Genome, Human

KW - Genomics

KW - Hepatocyte Nuclear Factor 3-beta

KW - Hepatocyte Nuclear Factor 3-gamma

KW - Histone Demethylases

KW - Homeodomain Proteins

KW - Humans

KW - Mice

KW - Mutation

KW - Nuclear Proteins

KW - Pancreatic Neoplasms

KW - Prognosis

KW - Receptors, Cytoplasmic and Nuclear

KW - Survival Analysis

KW - Trans-Activators

KW - Transcription Factors

KW - Transcription, Genetic

KW - Transcriptome

KW - Tumor Suppressor Protein p53

KW - Tumor Suppressor Proteins

KW - Zebrafish Proteins

UR - http://hdl.handle.net/10807/172586

U2 - 10.1038/nature16965

DO - 10.1038/nature16965

M3 - Article

SN - 0028-0836

VL - 531

SP - 47

EP - 52

JO - Nature

JF - Nature

ER -

Genomic analyses identify molecular subtypes of pancreatic cancer

Abstract

Keywords

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