Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

被引：1606

作者：

Biankin, Andrew V. ^{[2
,3
,4
,5
]}

Waddell, Nicola ^{[1
]}

Kassahn, Karin S. ^{[1
]}

Gingras, Marie-Claude ^{[6
,7
]}

Muthuswamy, Lakshmi B. ^{[8
]}

Johns, Amber L. ^{[2
,3
]}

Miller, David K. ^{[1
]}

Wilson, Peter J. ^{[1
]}

Patch, Ann-Marie ^{[1
]}

Wu, Jianmin ^{[2
,3
]}

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

Cowley, Mark J. ^{[2
,3
]}

Gardiner, Brooke B. ^{[1
]}

Song, Sarah ^{[1
]}

Harliwong, Ivon ^{[1
]}

Idrisoglu, Senel ^{[1
]}

Nourse, Craig ^{[1
]}

Nourbakhsh, Ehsan ^{[1
]}

Manning, Suzanne ^{[1
]}

Wani, Shivangi ^{[1
]}

Gongora, Milena ^{[1
]}

Pajic, Marina ^{[2
,3
]}

Scarlett, Christopher J. ^{[2
,3
,9
]}

Gill, Anthony J. ^{[2
,3
,10
,11
]}

Pinho, Andreia V. ^{[2
,3
]}

Rooman, Ilse ^{[2
,3
]}

Anderson, Matthew ^{[1
]}

Holmes, Oliver ^{[1
]}

Leonard, Conrad ^{[1
]}

Taylor, Darrin ^{[1
]}

Wood, Scott ^{[1
]}

Xu, Qinying ^{[1
]}

Nones, Katia ^{[1
]}

Fink, J. Lynn ^{[1
]}

Christ, Angelika ^{[1
]}

Bruxner, Tim ^{[1
]}

Cloonan, Nicole ^{[1
]}

Kolle, Gabriel ^{[12
]}

Newell, Felicity ^{[1
]}

Pinese, Mark ^{[2
,3
]}

Mead, R. Scott ^{[2
,3
,13
]}

Humphris, Jeremy L. ^{[2
,3
]}

Kaplan, Warren ^{[2
,3
]}

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

Colvin, Emily K. ^{[2
,3
]}

Nagrial, Adnan M. ^{[2
,3
]}

Humphrey, Emily S. ^{[2
,3
]}

Chou, Angela ^{[2
,3
,13
]}

Chin, Venessa T. ^{[2
,3
]}

Chantrill, Lorraine A. ^{[2
,3
]}

机构：

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

[2] Kinghorn Canc Ctr, Darlinghurst, NSW, Australia

[3] Garvan Inst Med Res, Canc Res Program, Sydney, NSW 2010, Australia

[4] Bankstown Hosp, Dept Surg, Sydney, NSW 2200, Australia

[5] Univ New S Wales, Fac Med, S Western Sydney Clin Sch, Liverpool, NSW 2170, Australia

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

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

[8] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

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

[10] Royal N Shore Hosp, Dept Anat Pathol, Sydney, NSW 2065, Australia

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

[12] Life Technol, Brisbane, Qld 4000, Australia

[13] St Vincents Hosp, Dept Anat Pathol, Sydney, NSW 2010, Australia

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

[15] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia

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

[17] Fremantle Hosp, Dept Surg, Fremantle, WA 6160, Australia

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

[19] Univ Queensland, Princess Alexandra Hosp, Dept Surg, Woollongabba, Qld 4102, Australia

[20] Univ Western Australia, Sch Surg M507, Nedlands, WA 6009, Australia

[21] St John God Pathol, Subiaco, WA 6008, Australia

[22] Baylor Coll Med, Elkins Pancreas Ctr, Houston, TX 77030 USA

[23] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA

[24] Univ Hlth Network, Toronto, ON M5G 2C4, Canada

[25] Mayo Clin, Rochester, MN 55905 USA

[26] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada

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

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

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

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

[31] Univ & Hosp Trust Verona, Dept Surg & Oncol, I-37134 Verona, Italy

[32] Univ Calif San Francisco, Div Hematol & Oncol, San Francisco, CA 94115 USA

[33] Methodist Hosp, Res Inst, Canc Res Program, Houston, TX 77030 USA

[34] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England

[35] Dept Oncol, Cambridge CB2 0RE, England

[36] Wellcome Trust Sanger Inst, Hinxton CB10 1HH, England

[37] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA

[38] Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands

[39] Univ New S Wales, Fac Med, St Vincents Clin Sch, Sydney, NSW 2010, Australia

来源：

NATURE | 2012年 / 491卷 / 7424期

基金：

加拿大创新基金会; 英国惠康基金; 英国医学研究理事会;

关键词：

SOMATIC MUTATIONS; TUMOR; INSTABILITY; EXPRESSION; RESECTION; ROLES;

D O I：

10.1038/nature11547

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：

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n=142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

引用

页码：399 / 405

页数：7

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