Abstract
The genetic component of breast cancer predisposition remains largely unexplained. Candidate gene case–control resequencing has identified predisposition genes characterised by rare, protein truncating mutations that confer moderate risks of disease. In theory, exome sequencing should yield additional genes of this class. Here, we explore the feasibility and design considerations of this approach. We performed exome sequencing in 50 individuals with familial breast cancer, applying frequency and protein function filters to identify variants most likely to be pathogenic. We identified 867,378 variants that passed the call quality filters of which 1,296 variants passed the frequency and protein truncation filters. The median number of validated, rare, protein truncating variants was 10 in individuals with, and without, mutations in known genes. The functional candidacy of mutated genes was similar in both groups. Without prior knowledge, the known genes would not have been recognisable as breast cancer predisposition genes. Everyone carries multiple rare mutations that are plausibly related to disease. Exome sequencing in common conditions will therefore require intelligent sample and variant prioritisation strategies in large case–control studies to deliver robust genetic evidence of disease association.
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Abbreviations
- RR:
-
Relative risk
- FBCS:
-
Familial breast cancer study
- PTV:
-
Protein truncating variant
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Acknowledgements
We thank all the patients and families who participated in the research. We thank Bernadette Ebbs for assistance in DNA extraction and running the ABI sequencers. We thank Margaret Warren-Perry, Anna Zachariou, Jessie Bull, Darshna Dudakia, Jessie Bull and Rachel Linger for coordination of recruitment and sample collection, and Ann Strydom for assistance with the manuscript. We are very grateful to all the clinicians and counsellors in the Breast Cancer Susceptibility Collaboration UK (BCSC) that have contributed to the recruitment and collection of the FBCS samples. The full list is the Supplementary Appendix. This work was supported by the US Military Acquisition (ACQ) Activity, Era of Hope Award (W81XWH-05-1-0204), Cancer Research UK (C8620/A8372 and C8620/A8857) and the Institute of Cancer Research (UK). We acknowledge the National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute of Health Research Specialist Biomedical Research Centre for Cancer. K.S. is supported by the Michael and Betty Kadoorie Cancer Genetics Research Programme.
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NHS National Research Ethics Service (MREC/01/2/18).
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Snape, K., Ruark, E., Tarpey, P. et al. Predisposition gene identification in common cancers by exome sequencing: insights from familial breast cancer. Breast Cancer Res Treat 134, 429–433 (2012). https://doi.org/10.1007/s10549-012-2057-x
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DOI: https://doi.org/10.1007/s10549-012-2057-x