Mutational landscape and significance across 12 major cancer types

被引：3361

作者：

Kandoth, Cyriac ^{[1
]}

McLellan, Michael D. ^{[1
]}

Vandin, Fabio ^{[2
]}

Ye, Kai ^{[1
,3
]}

Niu, Beifang ^{[1
]}

Lu, Charles ^{[1
]}

Xie, Mingchao ^{[1
]}

Zhang, Qunyuan ^{[1
,3
]}

McMichael, Joshua F. ^{[1
]}

Wyczalkowski, Matthew A. ^{[1
]}

Leiserson, Mark D. M. ^{[2
]}

Miller, Christopher A. ^{[1
]}

Welch, John S. ^{[4
,5
]}

Walter, Matthew J. ^{[4
,5
]}

Wendl, Michael C. ^{[1
,3
,6
]}

Ley, Timothy J. ^{[1
,3
,4
,5
]}

Wilson, Richard K. ^{[1
,3
,5
]}

Raphael, Benjamin J. ^{[2
]}

Ding, Li ^{[1
,3
,4
,5
]}

机构：

[1] Washington Univ, Genome Inst, St Louis, MO 63108 USA

[2] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA

[3] Washington Univ, Dept Genet, St Louis, MO 63108 USA

[4] Washington Univ, Dept Med, St Louis, MO 63108 USA

[5] Washington Univ, Siteman Canc Ctr, St Louis, MO 63108 USA

[6] Washington Univ, Dept Math, St Louis, MO 63108 USA

来源：

NATURE | 2013年 / 502卷 / 7471期

基金：

美国国家科学基金会;

关键词：

SOMATIC POINT MUTATIONS; BRCA2; MUTATIONS; HUMAN BREAST; SURVIVAL; PATHWAYS; ASSOCIATION; DISCOVERY; EVOLUTION; PBRM1;

D O I：

10.1038/nature12634

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：

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known(for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/beta-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

引用

页码：333 / +

页数：20

共 38 条

[1] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[2] Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer [J].

Bolton, Kelly L. ;

Chenevix-Trench, Georgia ;

Goh, Cindy ;

Sadetzki, Siegal ;

Ramus, Susan J. ;

Karlan, Beth Y. ;

Lambrechts, Diether ;

Despierre, Evelyn ;

Barrowdale, Daniel ;

McGuffog, Lesley ;

Healey, Sue ;

Easton, Douglas F. ;

Sinilnikova, Olga ;

Benitez, Javier ;

Garcia, Maria J. ;

Neuhausen, Susan ;

Gail, Mitchell H. ;

Hartge, Patricia ;

Peock, Susan ;

Frost, Debra ;

Evans, Gareth ;

Eeles, Rosalind ;

Godwin, Andrew K. ;

Daly, Mary B. ;

Kwong, Ava ;

Ma, Edmond S. K. ;

Lazaro, Conxi ;

Blanco, Ignacio ;

Montagna, Marco ;

D'Andrea, Emma ;

Nicoletto, Maria Ornella ;

Johnatty, Sharon E. ;

Krueger, Susanne ;

Jensen, Allan ;

Hogdall, Estrid ;

Goode, Ellen L. ;

Fridley, Brooke L. ;

Loud, Jennifer T. ;

Greene, Mark H. ;

Mai, Phuong L. ;

Chetrit, Angela ;

Lubin, Flora ;

Hirsh-Yechezkel, Galit ;

Glendon, Gord ;

Andrulis, Irene L. ;

Toland, Amanda E. ;

Senter, Leigha ;

Gore, Martin E. ;

Gourley, Charlie ;

Michie, Caroline O. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2012, 307 (04) :382-390

[3] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

[4] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

[5] The Biology of Chromatin Remodeling Complexes [J].

Clapier, Cedric R. ;

Cairns, Bradley R. .

ANNUAL REVIEW OF BIOCHEMISTRY, 2009, 78 :273-304

[6] Comprehensivemolecular characterization of clear cell renal cell carcinoma [J].

Creighton, Chad J. ;

Morgan, Margaret ;

Gunaratne, Preethi H. ;

Wheeler, David A. ;

Gibbs, Richard A. ;

Robertson, A. Gordon ;

Chu, Andy ;

Beroukhim, Rameen ;

Cibulskis, Kristian ;

Signoretti, Sabina ;

Vandin, Fabio ;

Wu, Hsin-Ta ;

Raphael, Benjamin J. ;

Verhaak, Roel G. W. ;

Tamboli, Pheroze ;

Torres-Garcia, Wandaliz ;

Akbani, Rehan ;

Weinstein, John N. ;

Reuter, Victor ;

Hsieh, James J. ;

Brannon, A. Rose ;

Hakimi, A. Ari ;

Jacobsen, Anders ;

Ciriello, Giovanni ;

Reva, Boris ;

Ricketts, Christopher J. ;

Linehan, W. Marston ;

Stuart, Joshua M. ;

Rathmell, W. Kimryn ;

Shen, Hui ;

Laird, Peter W. ;

Muzny, Donna ;

Davis, Caleb ;

Morgan, Margaret ;

Xi, Liu ;

Chang, Kyle ;

Kakkar, Nipun ;

Trevino, Lisa R. ;

Benton, Susan ;

Reid, Jeffrey G. ;

Morton, Donna ;

Doddapaneni, Harsha ;

Han, Yi ;

Lewis, Lora ;

Dinh, Huyen ;

Kovar, Christie ;

Zhu, Yiming ;

Santibanez, Jireh ;

Wang, Min ;

Hale, Walker .

NATURE, 2013, 499 (7456) :43-+

[7] MuSiC: Identifying mutational significance in cancer genomes [J].

Dees, Nathan D. ;

Zhang, Qunyuan ;

Kandoth, Cyriac ;

Wendl, Michael C. ;

Schierding, William ;

Koboldt, Daniel C. ;

Mooney, Thomas B. ;

Callaway, Matthew B. ;

Dooling, David ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Ding, Li .

GENOME RESEARCH, 2012, 22 (08) :1589-1598

[8] Somatic mutations affect key pathways in lung adenocarcinoma [J].

Ding, Li ;

Getz, Gad ;

Wheeler, David A. ;

Mardis, Elaine R. ;

McLellan, Michael D. ;

Cibulskis, Kristian ;

Sougnez, Carrie ;

Greulich, Heidi ;

Muzny, Donna M. ;

Morgan, Margaret B. ;

Fulton, Lucinda ;

Fulton, Robert S. ;

Zhang, Qunyuan ;

Wendl, Michael C. ;

Lawrence, Michael S. ;

Larson, David E. ;

Chen, Ken ;

Dooling, David J. ;

Sabo, Aniko ;

Hawes, Alicia C. ;

Shen, Hua ;

Jhangiani, Shalini N. ;

Lewis, Lora R. ;

Hall, Otis ;

Zhu, Yiming ;

Mathew, Tittu ;

Ren, Yanru ;

Yao, Jiqiang ;

Scherer, Steven E. ;

Clerc, Kerstin ;

Metcalf, Ginger A. ;

Ng, Brian ;

Milosavljevic, Aleksandar ;

Gonzalez-Garay, Manuel L. ;

Osborne, John R. ;

Meyer, Rick ;

Shi, Xiaoqi ;

Tang, Yuzhu ;

Koboldt, Daniel C. ;

Lin, Ling ;

Abbott, Rachel ;

Miner, Tracie L. ;

Pohl, Craig ;

Fewell, Ginger ;

Haipek, Carrie ;

Schmidt, Heather ;

Dunford-Shore, Brian H. ;

Kraja, Aldi ;

Crosby, Seth D. ;

Sawyer, Christopher S. .

NATURE, 2008, 455 (7216) :1069-1075

[9] Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing [J].

Ding, Li ;

Ley, Timothy J. ;

Larson, David E. ;

Miller, Christopher A. ;

Koboldt, Daniel C. ;

Welch, John S. ;

Ritchey, Julie K. ;

Young, Margaret A. ;

Lamprecht, Tamara ;

McLellan, Michael D. ;

McMichael, Joshua F. ;

Wallis, John W. ;

Lu, Charles ;

Shen, Dong ;

Harris, Christopher C. ;

Dooling, David J. ;

Fulton, Robert S. ;

Fulton, Lucinda L. ;

Chen, Ken ;

Schmidt, Heather ;

Kalicki-Veizer, Joelle ;

Magrini, Vincent J. ;

Cook, Lisa ;

McGrath, Sean D. ;

Vickery, Tammi L. ;

Wendl, Michael C. ;

Heath, Sharon ;

Watson, Mark A. ;

Link, Daniel C. ;

Tomasson, Michael H. ;

Shannon, William D. ;

Payton, Jacqueline E. ;

Kulkarni, Shashikant ;

Westervelt, Peter ;

Walter, Matthew J. ;

Graubert, Timothy A. ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

DiPersio, John F. .

NATURE, 2012, 481 (7382) :506-510

[10] The Pediatric Cancer Genome Project [J].

Downing, James R. ;

Wilson, Richard K. ;

Zhang, Jinghui ;

Mardis, Elaine R. ;

Pui, Ching-Hon ;

Ding, Li ;

Ley, Timothy J. ;

Evans, William E. .

NATURE GENETICS, 2012, 44 (06) :619-622

← 1 2 3 4 →