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Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer

Author

Listed:
  • Daniel Chubb

    (The Institute of Cancer Research)

  • Peter Broderick

    (The Institute of Cancer Research)

  • Sara E. Dobbins

    (The Institute of Cancer Research)

  • Matthew Frampton

    (The Institute of Cancer Research)

  • Ben Kinnersley

    (The Institute of Cancer Research)

  • Steven Penegar

    (The Institute of Cancer Research)

  • Amy Price

    (The Institute of Cancer Research)

  • Yussanne P. Ma

    (The Institute of Cancer Research
    Present address: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada, V5Z 4S6.)

  • Amy L. Sherborne

    (The Institute of Cancer Research)

  • Claire Palles

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Maria N. Timofeeva

    (Centre for Population Health Sciences, University of Edinburgh)

  • D. Timothy Bishop

    (Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, St James’s University Hospital)

  • Malcolm G. Dunlop

    (Centre for Population Health Sciences, University of Edinburgh)

  • Ian Tomlinson

    (Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford)

  • Richard S. Houlston

    (The Institute of Cancer Research
    The Institute of Cancer Research)

Abstract

Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enshrined in high-impact rare alleles, which are mechanistically and clinically important. In this study, we assay the impact of rare germline mutations on CRC, analysing high-coverage exome sequencing data on 1,006 early-onset familial CRC cases and 1,609 healthy controls, with additional sequencing and array data on up to 5,552 cases and 6,792 controls. We identify highly penetrant rare mutations in 16% of familial CRC. Although the majority of these reside in known genes, we identify POT1, POLE2 and MRE11 as candidate CRC genes. We did not identify any coding low-frequency alleles (1–5%) with moderate effect. Our study clarifies the genetic architecture of CRC and probably discounts the existence of further major high-penetrance susceptibility genes, which individually account for >1% of the familial risk. Our results inform future study design and provide a resource for contextualizing the impact of new CRC genes.

Suggested Citation

  • Daniel Chubb & Peter Broderick & Sara E. Dobbins & Matthew Frampton & Ben Kinnersley & Steven Penegar & Amy Price & Yussanne P. Ma & Amy L. Sherborne & Claire Palles & Maria N. Timofeeva & D. Timothy , 2016. "Rare disruptive mutations and their contribution to the heritable risk of colorectal cancer," Nature Communications, Nature, vol. 7(1), pages 1-7, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11883
    DOI: 10.1038/ncomms11883
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