Genomic analyses identify molecular subtypes of pancreatic cancer

被引：2614

作者：

Bailey, Peter ^{[1
,2
]}

Chang, David K. ^{[2
,3
,4
,5
,6
]}

Nones, Katia ^{[1
,7
]}

Johns, Amber L. ^{[3
,4
]}

Patch, Ann-Marie ^{[1
,7
]}

Gingras, Marie-Claude ^{[8
,9
,10
]}

Miller, David K. ^{[1
,3
,4
]}

Christ, Angelika N. ^{[1
]}

Bruxner, Tim J. C. ^{[1
]}

Quinn, Michael C. ^{[1
,7
]}

Nourse, Craig ^{[1
,2
]}

Murtaugh, L. Charles ^{[11
]}

Harliwong, Ivon ^{[1
]}

Idrisoglu, Senel ^{[1
]}

Manning, Suzanne ^{[1
]}

Nourbakhsh, Ehsan ^{[1
]}

Wani, Shivangi ^{[1
,7
]}

Fink, Lynn ^{[1
]}

Holmes, Oliver ^{[1
,7
]}

Chin, Vencssa ^{[3
,4
]}

Anderson, Matthew J. ^{[1
]}

Kazakoff, Stephen ^{[1
,7
]}

Leonard, Conrad ^{[1
,7
]}

Newell, Felicity ^{[1
]}

Waddell, Nick ^{[1
]}

Wood, Scott ^{[1
,7
]}

Xu, Qinying ^{[1
,7
]}

Wilson, Peter J. ^{[1
]}

Cloonan, Nicole ^{[1
,7
]}

Kassahn, Karin S. ^{[1
,12
,13
]}

Taylor, Darrin ^{[1
]}

Quek, Kelly ^{[1
]}

Robertson, Alan ^{[1
]}

Pantano, Lorena ^{[14
]}

Mincarelli, Laura ^{[2
]}

Sanchez, Luis N. ^{[2
]}

Evers, Lisa ^{[2
]}

Wu, Jianmin ^{[3
,4
]}

Pinese, Mark ^{[3
,4
]}

Cowley, Mark J. ^{[3
,4
]}

Jones, Marc D. ^{[2
,3
,4
]}

Colvin, Emily K. ^{[3
,4
]}

Nagrial, Adnan M. ^{[3
,4
]}

Humphrey, Emily S. ^{[3
,4
]}

Chantrill, Lorraine A. ^{[3
,4
,15
]}

Mawson, Amanda ^{[3
,4
]}

Humphris, Jeremy ^{[3
,4
]}

Chou, Angela ^{[3
,4
,16
]}

Pajic, Marina ^{[3
,4
,17
]}

Scarlett, Christopher J. ^{[3
,4
,18
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Queensland Ctr Med Genom, Brisbane, Qld 4072, Australia

[2] Univ Glasgow, Inst Canc Sci, Wolfson Wohl Canc Res Ctr, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland

[3] Kinghorn Canc Ctr, 370 Victoria St, Darlinghurst, NSW 2010, Australia

[4] Garvan Inst Med Res, Canc Res Program, 384 Victoria St, Sydney, NSW 2010, Australia

[5] Bankstown Hosp, Dept Surg, Eldridge Rd, Sydney, NSW 2200, Australia

[6] Univ New S Wales, Fac Med, South Western Sydney Clin Sch, Liverpool, Merseyside 2170, England

[7] QIMR Berghofer Med Res Inst, Herston, Qld 4006, Australia

[8] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA

[9] Baylor Coll Med, Michael DeBakey Dept Surg, Houston, TX 77030 USA

[10] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[11] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA

[12] SA Pathol, Genet & Mol Pathol, Adelaide, SA 5000, Australia

[13] Univ Adelaide, Sch Biol Sci, Adelaide, SA 5000, Australia

[14] Harvard Univ, TH Chan Sch Publ Hlth, Harvard Chan Bioinformat Core, Boston, MA 02115 USA

[15] Campbelltown Hosp, Macarthur Canc Therapy Ctr, Campbelltown, NSW 2560, Australia

[16] St Vincents Hosp, SydPath, Dept Pathol, Sydney, NSW 2010, Australia

[17] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2052, Australia

[18] Univ Newcastle, Sch Environm & Life Sci, Ourimbah, NSW 2258, Australia

[19] Royal N Shore Hosp, Dept Surg, Sydney, NSW 2065, Australia

[20] Univ Sydney, Sydney, NSW 2006, Australia

[21] Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Camperdown, NSW 2050, Australia

[22] Univ Western Sydney, Sch Med, Penrith, NSW 2175, Australia

[23] Fiona Stanley Hosp, Robin Warren Dr, Murdoch, WA 6150, Australia

[24] Royal Adelaide Hosp, Dept Gastroenterol, Adelaide, SA 5000, Australia

[25] Princess Alexandra Hosp, Dept Surg, Ipswich Rd, Woollongabba, Qld 4102, Australia

[26] Univ Western Australia, Sch Surg M507, 35 Stirling Hwy, Nedlands, WA 6009, Australia

[27] St John God Pathol, 12 Salvado Rd, Subiaco, WA 6008, Australia

[28] Univ Glasgow, Glasgow Royal Infirm, Coll Med Vet & Life Sci, Sch Med,Acad Unit Surg, Glasgow G4 OSF, Lanark, Scotland

[29] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow G31 2ER, Lanark, Scotland

[30] Beatson West Scotland Canc Ctr, Dept Med Oncol, 1053 Great Western Rd, Glasgow G12 0YN, Lanark, Scotland

[31] Greater Glasgow & Clyde NHS, So Gen Hosp, Dept Pathol, Glasgow G51 4TF, Lanark, Scotland

[32] So Gen Hosp, Dept Pathol, GGC Biorepository, 1345 Govan Rd, Glasgow G51 4TY, Lanark, Scotland

[33] Tech Univ Dresden, Dept Surg, Fetscherstr 74, D-01307 Dresden, Germany

[34] UT MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[35] UT MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA

[36] Mem Sloan Kettering Canc Ctr, David M Rubenstein Pancreat Canc Res Ctr, New York, NY 10065 USA

[37] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[38] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21231 USA

[39] Johns Hopkins Univ, Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Surg, Baltimore, MD 21231 USA

[40] Univ & Hosp Trust Verona, ARC Net Appl Res Canc Ctr, I-37134 Verona, Italy

[41] Univ Verona, Dept Pathol & Diagnost, I-37134 Verona, Italy

[42] Univ & Hosp Trust Verona, Pancreas Inst, Dept Surg, I-37134 Verona, Italy

[43] Univ & Hosp Trust Verona, Ctr Comprehens Canc, Dept Med Oncol, I-37134 Verona, Italy

[44] Mayo Clin, Rochester, MN 55905 USA

[45] Baylor Coll Med, Elkins Pancreas Ctr, One Baylor Plaza,MS226, Houston, TX 77030 USA

[46] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[47] Univ Glasgow, Inst Canc Sci, Glasgow G12 8QQ, Lanark, Scotland

[48] Univ Melbourne, Melbourne, Vic 3010, Australia

[49] Univ Klinikum Erlangen, Dept Surg, D-91054 Erlangen, Germany

来源：

NATURE | 2016年 / 531卷 / 7592期

基金：

英国医学研究理事会; 英国惠康基金; 欧洲研究理事会;

关键词：

DUCTAL ADENOCARCINOMA; MUTATIONS; PACKAGE; TUMOR; DIFFERENTIATION; METASTASIS; PATHWAYS;

D O I：

10.1038/nature16965

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, 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 TP63 Delta N 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.

引用

页码：47 / +

页数：19

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