Discovery and saturation analysis of cancer genes across 21 tumour types
Michael S Lawrence, Petar Stojanov, Craig H Mermel, James T Robinson, Levi A Garraway, Todd R Golub, Matthew Meyerson, Stacey B Gabriel, Eric S Lander, Gad Getz, Michael S Lawrence, Petar Stojanov, Craig H Mermel, James T Robinson, Levi A Garraway, Todd R Golub, Matthew Meyerson, Stacey B Gabriel, Eric S Lander, Gad Getz
Abstract
Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.
Figures
References
- Garraway LA, Lander ES. Lessons from the cancer genome. Cell. 2013;153:17–37.
- Vogelstein B, et al. Cancer genome landscapes. Science. 2013;339:1546–1558.
- Imielinski M, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150:1107–1120.
- Carter SL, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30:413–421.
- Cibulskis K, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213–219.
- Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–218.
- Zack TI, et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet. 2013;45:1134–1140.
- Lohr JG, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109:3879–3884.
- Cancer Genome Atlas Research, N et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.
- Kandoth C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–339.
- Tamborero D, et al. Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep. 2013;3:2650.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
- Ferlay J, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917.
Source: PubMed