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Mutational heterogeneity in cancer and the search for new cancer-associated genes

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Abstract

Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer1,2,3,4,5,6,7,8,9. These studies involve the sequencing of matched tumour–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour–normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

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Figure 1: Somatic mutation frequencies observed in exomes from 3,083 tumour–normal pairs.
Figure 2: Radial spectrum plot of the 2,892 tumour samples with at least 10 coding mutations.
Figure 3: Mutation rate varies widely across the genome and correlates with DNA replication time and expression level.

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Acknowledgements

This work was conducted as part of TCGA, a project of the National Cancer Institute and National Human Genome Research Institute. This work was conducted as part of the Slim Initiative for Genomic Medicine, a joint US–Mexico project founded by the Carlos Slim Health Institute. Support to D.A.G. and S.A.R. was through the Intramural Research Program of the National Institute of Environmental Health Sciences (National Institutes of Health, United States Department of Health and Human Services) project ES065073 (principal investigator M. Resnick).

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G.G., E.S.L., S.S., D.A.G., T.R.G., M.M., L.A.G., A.J.B., K.S., J.A.B., C.W.M.R., S.B.G., C.J.W., S.A.M., J.M.-Z. and A.H.-M. conceived the project and provided leadership. C.So., L.A., E.N., E.S., M.L.C., D.A., W.W. and K.A. provided project management. W.W., K.A., T.F., R.O. and M.P. planned and carried out DNA sequencing and genetic analysis. T.F., D.V., G.S., M.N., D.D., P.L., L.L. and D.I.H. developed and engineered software to support the project. M.S.L., P.S., P.P., G.V.K., K.C., A.S., S.L.C., C.St., C.H.M., S.A.R., A.Ki., P.S.H., A.M., Y.D., L.Z., A.H.R., T.J.P., N.S., E.H., J.K., M.I., B.H., E.H., S.B., A.M.D., J.L., D.-A.L., C.J.W., J.M.-Z., A.H.-M., A.Ko., S.A.M., R.S.L., J.M., B.C., A.J.B. and D.A.G. analysed the data and contributed to scientific discussions. M.S.L., P.S., P.P., E.S.L. and G.G. wrote the paper.

Corresponding authors

Correspondence to Eric S. Lander or Gad Getz.

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Supplementary Information

This file contains Supplementary Figures 1-11, Supplementary Methods 0-3, legends for Supplementary Tables 1-7 (see separate excel file for Supplementary Tables) and additional references. (PDF 1974 kb)

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Lawrence, M., Stojanov, P., Polak, P. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013). https://doi.org/10.1038/nature12213

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