Genomic analyses identify molecular subtypes of pancreatic cancer

Australian Pancreatic Cancer Genome Initiative

doi:10.1038/nature16965

Genomic analyses identify molecular subtypes of pancreatic cancer

Australian Pancreatic Cancer Genome Initiative

Research output: Contribution to journal › Article › peer-review

1336 Scopus citations

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.

Original language	English (US)
Pages (from-to)	47-52
Number of pages	6
Journal	Nature
Volume	531
Issue number	7592
DOIs	https://doi.org/10.1038/nature16965
State	Published - Mar 3 2016

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@article{f37b5b26c7924280b07aaaf0496cda74,

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 = "{Australian Pancreatic Cancer Genome Initiative} and 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 Debabrata Mukhopadhyay and Petersen, {Gloria M.}",

year = "2016",

month = mar,

day = "3",

doi = "10.1038/nature16965",

language = "English (US)",

volume = "531",

pages = "47--52",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7592",

}

TY - JOUR

T1 - Genomic analyses identify molecular subtypes of pancreatic cancer

AU - Australian Pancreatic Cancer Genome Initiative

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 - Mukhopadhyay, Debabrata

AU - Petersen, Gloria M.

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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U2 - 10.1038/nature16965

DO - 10.1038/nature16965

M3 - Article

C2 - 26909576

AN - SCOPUS:84960194345

SN - 0028-0836

VL - 531

SP - 47

EP - 52

JO - Nature

JF - Nature

IS - 7592

ER -

Genomic analyses identify molecular subtypes of pancreatic cancer

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