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Cancer genetics, precision prevention and a call to action

Nature Geneticsvolume 50pages12121218 (2018) | Download Citation

Abstract

More than 15 years have passed since the identification, through linkage, of ‘first-wave’ susceptibility genes for common cancers (BRCA1, BRCA2, MLH1 and MSH2). These genes have strong frequency-penetrance profiles, such that the associated clinical utility probably remains relevant regardless of the context of ascertainment. ‘Second-wave’ genes, not tractable by linkage, were subsequently identified by mutation screening of candidate genes (PALB2, ATM, CHEK2, BRIP1, RAD51C and RAD51D). Their innately weaker frequency-penetrance profiles have rendered delineation of cancer associations, risks and variant pathogenicity challenging, thereby compromising their clinical application. Early germline exome-sequencing endeavors for common cancers did not yield the long-anticipated slew of ‘next-wave’ genes but instead implied a highly polygenic genomic architecture requiring much larger experiments to make any substantive inroads into gene discovery. As such, the ‘genetic economics’ of frequency penetrance clearly indicates that focused identification of carriers of first-wave-gene mutations is most impactful for cancer control. With screening, prevention and early detection at the forefront of the cancer management agenda, we propose that the time is nigh for the initiation of national population-testing programs to identify carriers of first-wave gene mutation carriers. To fully deliver a precision prevention program, long-term, large-scale mutation studies that capture longitudinal clinical data and serial biosamples are required.

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Acknowledgements

We thank our many colleagues for decades of interesting discussions around these themes, in particular W. Foulkes, M. Tischkowitz, H. Hanson, A. Taylor, K. Snape and A. Kulkani for their invaluable and wise thoughts. We also thank D. Easton (University of Cambridge, UK) and P. Devilee (Leiden University Medical Center, the Netherlands) for providing the data used to generate Fig. 1a. R.S.H. is supported by Cancer Research UK (C1298/A8362 Bobby Moore Fund for Cancer Research UK). C.T. is supported by the Movember Foundation.

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  1. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK

    • Clare Turnbull
    • , Amit Sud
    •  & Richard S. Houlston
  2. William Harvey Research Institute, Queen Mary University, London, UK

    • Clare Turnbull
  3. Guys and St Thomas Foundation NHS Trust, London, UK

    • Clare Turnbull
  4. Public Health England, National Cancer Registration and Analysis Service, London, UK

    • Clare Turnbull

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C.T., A.S. and R.S.H. researched, reviewed, drafted and edited the manuscript. A.S. and C.T. generated the images.

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The authors declare no competing interests.

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Correspondence to Clare Turnbull.

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https://doi.org/10.1038/s41588-018-0202-0