Abstract
Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers1. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time—to our knowledge—in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC2,3 showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.
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Aligned exome/genome sequence data, RNA-seq data and Affymetrix SNP6.0 data sets are available at the European Genome-phenome Archive (http://www.ebi.ac.uk/ega/) under study accession number EGAS00001000132. Normal reference RNA-seq datasets are available at the NCBI Short Read Archive (http://www.ncbi.nlm.nih.gov/Traces) under study accession number SRP000930.
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Acknowledgements
The support of the BC Cancer Agency Tumour Bank, CBCF Breast Tumour Bank Alberta and the Addenbrookes Tumour bank (supported by NIHR and ECMC) is acknowledged. Technical support is acknowledged from the Centre for Translational Genomics, the Michael Smith Genome Sciences Centre technical group, the BCCA Flow Cytometry Core Facility in the Terry Fox Laboratory and the Cancer Research UK Cambridge Research Institute. Supported by the BC Cancer Foundation, US Department of Defense CDMRP program, Canadian Breast Cancer Foundation (BC Yukon) (to S.A. and S.S.), Michael Smith Foundation for Health Research (to S.S.), US National Institutes of Health (NIH) Roadmap Epigenomics Program, NIH grant 5U01ES017154-02 (to M.H., M.A.M., J.C. and T.T.), Cancer Research UK (to C. Caldas and P.D.P.) and the National Institute of General Medical Sciences (R01GM084875 to W.W.W.), the Canadian Breast Cancer Research Alliance and the Canadian Cancer Society (to S.A. and C.E.). We thank B. Reva, Y. Antipin and C. Sander (Memorial Sloan Kettering Cancer Center) for assistance with MutationAssessor, and G. Wu (Ontario Institute for Cancer Research) for assistance with Reactome.
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S.A., S.P.S., C. Caldas and M.A.M. designed and implemented the research plan and wrote the manuscript. S.P.S., A.R., R. Goya, G. Ha, J.D., G. Haffari, A. Bashashati, A. McPherson, K.S., A.C., R. Giuliany, A.H.-M., J.R., D.L., I.B., R.V., S.W.C., M.G., I.M.M., S.J., C. Curtis, O.M.R., P.D.P., V.B. and W.W.W. conducted bioinformatic analyses of the data and/or gave advice on analytic methodology. G.T. conducted histopathological review and immunohistohemistry. A.O., Y.Z., G.T., K.T., L.M.P., J.K., A.B., D.Y., A.T., N.D., T.Z., S.-F.C., K.M. and M.H. conducted sequencing or experimental validation of somatic aberrations. D.Y., A. Moradian, S.-W.G.C. and G.B.M. conducted proteome validation of splicing. P.W., K.G., S.C., S.-F.C., G.T., J.M., C. Caldas, P.D.P. and D.H. collected and interpreted clinical data. S.D., J.F.C., T.T., M.S., P.G. and C.J.E. contributed materials or reagents. K.H., V.T., T.H., M.H. and M.A.M. generated sequence data.
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This file contains legends for Supplementary Figures 1-12 (see pages 2-5), Supplementary Figures 1-12 (see pages 6-127), Supplementary Methods with additional references (see pages 128-140) and legends for Supplementary Tables 1-17 with additional references (see pages 142-145). (PDF 22432 kb)
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Shah, S., Roth, A., Goya, R. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012). https://doi.org/10.1038/nature10933
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DOI: https://doi.org/10.1038/nature10933
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