Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

被引：206

作者：

Nones, Katia ^{[1
,2
]}

Waddell, Nicola ^{[1
,2
]}

Wayte, Nicci ^{[3
]}

Patch, Ann-Marie ^{[1
]}

Bailey, Peter ^{[1
]}

Newell, Felicity ^{[1
]}

Holmes, Oliver ^{[1
,2
]}

Fink, J. Lynn ^{[1
]}

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

Tang, Yue Hang ^{[3
]}

Lampe, Guy ^{[4
]}

Quek, Kelly ^{[1
]}

Loffler, Kelly A. ^{[3
]}

Manning, Suzanne ^{[1
]}

Idrisoglu, Senel ^{[1
]}

Miller, David ^{[1
]}

Xu, Qinying ^{[1
,2
]}

Waddell, Nick ^{[1
]}

Wilson, Peter J. ^{[1
]}

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

Christ, Angelika N. ^{[1
]}

Harliwong, Ivon ^{[1
]}

Nourse, Craig ^{[1
]}

Nourbakhsh, Ehsan ^{[1
]}

Anderson, Matthew ^{[1
]}

Kazakoff, Stephen ^{[1
]}

Leonard, Conrad ^{[1
,2
]}

Wood, Scott ^{[1
,2
]}

Simpson, Peter T. ^{[2
,5
,6
]}

Reid, Lynne E. ^{[2
,5
]}

Krause, Lutz ^{[2
]}

Hussey, Damian J. ^{[7
]}

Watson, David I. ^{[7
]}

Lord, Reginald V. ^{[8
,9
]}

Nancarrow, Derek ^{[2
]}

Phillips, Wayne A. ^{[10
]}

Gotley, David ^{[11
]}

Smithers, B. Mark ^{[11
]}

Whiteman, David C. ^{[2
]}

Hayward, Nicholas K. ^{[2
]}

Campbell, Peter J. ^{[12
]}

Pearson, John V. ^{[1
,2
]}

Grimmond, Sean M. ^{[1
,13
]}

Barbour, Andrew P. ^{[3
,11
]}

机构：

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

[2] QIMR Berghofer Med Res Inst, Brisbane, Qld 4006, Australia

[3] Univ Queensland, Sch Med, Surg Oncol Grp, Princess Alexandra Hosp,Translat Res Inst, Brisbane, Qld 4102, Australia

[4] Princess Alexandra Hosp, Dept Anat Pathol, Brisbane, Qld 4102, Australia

[5] Univ Queensland, UQ Ctr Clin Res, Brisbane, Qld 4029, Australia

[6] Univ Queensland, Sch Med, Brisbane, Qld 4006, Australia

[7] Flinders Univ S Australia, Med Ctr, Dept Surg, Bedford Pk, SA 5042, Australia

[8] Univ Notre Dame, St Vincents Ctr Appl Med Res, Sydney, NSW 2011, Australia

[9] Univ New S Wales, Sydney, NSW 2011, Australia

[10] Peter MacCallum Canc Inst, Canc Res Div, Melbourne, Vic 3002, Australia

[11] Univ Queensland, Princess Alexandra Hosp, Sch Med, Dept Surg, Brisbane, Qld 4102, Australia

[12] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, Cambs, England

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

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

COPY-NUMBER ALTERATION; BARRETTS-ESOPHAGUS; MUTATIONAL PROCESSES; CANCER GENOMES; IN-VIVO; CHROMOTHRIPSIS; INSTABILITY; REARRANGEMENT; PATTERNS;

D O I：

10.1038/ncomms6224

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：

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n = 40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

引用

页数：9

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