Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

被引：130

作者：

Chubb, Daniel ^{[1
]}

Broderick, Peter ^{[1
]}

Dobbins, Sara E. ^{[1
]}

Frampton, Matthew ^{[1
]}

Kinnersley, Ben ^{[1
]}

Penegar, Steven ^{[1
]}

Price, Amy ^{[1
]}

Ma, Yussanne P. ^{[1
,6
]}

Sherborne, Amy L. ^{[1
]}

Palles, Claire ^{[2
]}

Timofeeva, Maria N. ^{[3
]}

Bishop, D. Timothy ^{[4
]}

Dunlop, Malcolm G. ^{[3
]}

Tomlinson, Ian ^{[2
]}

Houlston, Richard S. ^{[1
,5
]}

机构：

[1] Inst Canc Res, Div Genet & Epidemiol, London SM2 5NG, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Mol & Populat Genet Lab, Oxford OX3 7BN, England

[3] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh EH8 9AG, Midlothian, Scotland

[4] Univ Leeds, Leeds Inst Canc & Pathol, Sect Epidemiol & Biostat, St Jamess Univ Hosp, Leeds LS9 7TF, W Yorkshire, England

[5] Inst Canc Res, Div Pathol, London SM2 5NG, England

[6] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

GERMLINE MUTATIONS; VARIANTS; PREDISPOSE; GENE; ARCHITECTURE; METAANALYSIS; EXPRESSION; FRAMEWORK; ADENOMAS; POLE;

D O I：

10.1038/ncomms11883

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1-5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for 41% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.

引用

页数：7

共 34 条

[1]

Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors [J].

Al-Tassan, N ;

Chmiel, NH ;

Maynard, J ;

Fleming, N ;

Livingston, AL ;

Williams, GT ;

Hodges, AK ;

Davies, DR ;

David, SS ;

Sampson, JR ;

Cheadle, JR .

NATURE GENETICS, 2002, 30 (02) :227-232

[2]

Germline Mutations in Shelterin Complex Genes Are Associated With Familial Glioma [J].

Bainbridge, Matthew N. ;

Armstrong, Georgina N. ;

Gramatges, M. Monica ;

Bertuch, Alison A. ;

Jhangiani, Shalini N. ;

Doddapaneni, Harsha ;

Lewis, Lora ;

Tombrello, Joseph ;

Tsavachidis, Spyros ;

Liu, Yanhong ;

Jalali, Ali ;

Plon, Sharon E. ;

Lau, Ching C. ;

Parsons, Donald W. ;

Claus, Elizabeth B. ;

Barnholtz-Sloan, Jill ;

Il'yasova, Dora ;

Schildkraut, Joellen ;

Ali-Osman, Francis ;

Sadetzki, Siegal ;

Johansen, Christoffer ;

Houlston, Richard S. ;

Jenkins, Robert B. ;

Lachance, Daniel ;

Olson, Sara H. ;

Bernstein, Jonine L. ;

Merrell, Ryan T. ;

Wrensch, Margaret R. ;

Walsh, Kyle M. ;

Davis, Faith G. ;

Lai, Rose ;

Shete, Sanjay ;

Aldape, Kenneth ;

Amos, Christopher I. ;

Thompson, Patricia A. ;

Muzny, Donna M. ;

Gibbs, Richard A. ;

Melin, Beatrice S. ;

Bondy, Melissa L. .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2015, 107 (01)

[3]

The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website [J].

Bamford, S ;

Dawson, E ;

Forbes, S ;

Clements, J ;

Pettett, R ;

Dogan, A ;

Flanagan, A ;

Teague, J ;

Futreal, PA ;

Stratton, MR ;

Wooster, R .

BRITISH JOURNAL OF CANCER, 2004, 91 (02) :355-358

[4]

Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers [J].

Briggs, Sarah ;

Tomlinson, Ian .

JOURNAL OF PATHOLOGY, 2013, 230 (02) :148-153

[5]

A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families [J].

Calvete, Oriol ;

Martinez, Paula ;

Garcia-Pavia, Pablo ;

Benitez-Buelga, Carlos ;

Paumard-Hernandez, Beatriz ;

Fernandez, Victoria ;

Dominguez, Fernando ;

Salas, Clara ;

Romero-Laorden, Nuria ;

Garcia-Donas, Jesus ;

Carrillo, Jaime ;

Perona, Rosario ;

Carlos Trivino, Juan ;

Andres, Raquel ;

Maria Cano, Juana ;

Rivera, Barbara ;

Alonso-Pulpon, Luis ;

Setien, Fernando ;

Esteller, Manel ;

Rodriguez-Perales, Sandra ;

Bougeard, Gaelle ;

Frebourg, Tierry ;

Urioste, Miguel ;

Blasco, Maria A. ;

Benitez, Javier .

NATURE COMMUNICATIONS, 2015, 6

[6]

A framework for variation discovery and genotyping using next-generation DNA sequencing data [J].

DePristo, Mark A. ;

Banks, Eric ;

Poplin, Ryan ;

Garimella, Kiran V. ;

Maguire, Jared R. ;

Hartl, Christopher ;

Philippakis, Anthony A. ;

del Angel, Guillermo ;

Rivas, Manuel A. ;

Hanna, Matt ;

McKenna, Aaron ;

Fennell, Tim J. ;

Kernytsky, Andrew M. ;

Sivachenko, Andrey Y. ;

Cibulskis, Kristian ;

Gabriel, Stacey B. ;

Altshuler, David ;

Daly, Mark J. .

NATURE GENETICS, 2011, 43 (05) :491-+

[7]

Human Genome Sequencing Using Unchained Base Reads on Self-Assembling DNA Nanoarrays [J].

Drmanac, Radoje ;

Sparks, Andrew B. ;

Callow, Matthew J. ;

Halpern, Aaron L. ;

Burns, Norman L. ;

Kermani, Bahram G. ;

Carnevali, Paolo ;

Nazarenko, Igor ;

Nilsen, Geoffrey B. ;

Yeung, George ;

Dahl, Fredrik ;

Fernandez, Andres ;

Staker, Bryan ;

Pant, Krishna P. ;

Baccash, Jonathan ;

Borcherding, Adam P. ;

Brownley, Anushka ;

Cedeno, Ryan ;

Chen, Linsu ;

Chernikoff, Dan ;

Cheung, Alex ;

Chirita, Razvan ;

Curson, Benjamin ;

Ebert, Jessica C. ;

Hacker, Coleen R. ;

Hartlage, Robert ;

Hauser, Brian ;

Huang, Steve ;

Jiang, Yuan ;

Karpinchyk, Vitali ;

Koenig, Mark ;

Kong, Calvin ;

Landers, Tom ;

Le, Catherine ;

Liu, Jia ;

McBride, Celeste E. ;

Morenzoni, Matt ;

Morey, Robert E. ;

Mutch, Karl ;

Perazich, Helena ;

Perry, Kimberly ;

Peters, Brock A. ;

Peterson, Joe ;

Pethiyagoda, Charit L. ;

Pothuraju, Kaliprasad ;

Richter, Claudia ;

Rosenbaum, Abraham M. ;

Roy, Shaunak ;

Shafto, Jay ;

Sharanhovich, Uladzislau .

SCIENCE, 2010, 327 (5961) :78-81

[8]

Architecture of inherited susceptibility to common cancer [J].

Fletcher, Olivia ;

Houlston, Richard S. .

NATURE REVIEWS CANCER, 2010, 10 (05) :353-361

[9]

Implications of polygenic risk for personalised colorectal cancer screening [J].

Frampton, M. J. E. ;

Law, P. ;

Litchfield, K. ;

Morris, E. J. ;

Kerr, D. ;

Turnbull, C. ;

Tomlinson, I. P. ;

Houlston, R. S. .

ANNALS OF ONCOLOGY, 2016, 27 (03) :429-434

[10]

Improving the Assessment of the Outcome of Nonsynonymous SNVs with a Consensus Deleteriousness Score, Condel [J].

Gonzalez-Perez, Abel ;

Lopez-Bigas, Nuria .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 88 (04) :440-449

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