Review Article | Published:

Therapeutic implications of germline genetic findings in cancer

Nature Reviews Clinical Oncology (2019) | Download Citation

Abstract

Cancer is a genetic disease. To date, translational cancer genomics has focused largely on somatic alterations, driven by the desire to identify targets for personalized therapy. However, therapeutically relevant information is also latent within the germline genome. In addition to cancer susceptibility, alterations present in the germ line can determine responses to both targeted and more traditional anticancer therapies, as well as their toxicities. Despite the importance of these alterations, many algorithms designed to analyse somatic mutations conversely continue to subtract information on germline genetics during analysis. In the light of low actionable yields from somatic tumour testing, a need exists for diversification of the sources of potential therapeutic biomarkers. In this Review, we summarize the literature on the therapeutic potential of alterations in the germline genome. The therapeutic value of germline information will not only be manifest as improvements in treatment but will also drive greater levels of engagement and cooperation between traditional oncology services and familial risk management clinics.

Key points

  • Expanded application of genomic sequencing has revealed a substantial burden of germline variants across a range of tumour histologies.

  • The relevance of germline variations to therapy selection is only now being fully realized.

  • The clonal nature of germline alterations makes them ideal predictive biomarkers.

  • A growing appreciation of the therapeutic relevance of germline variations is likely to increase the demand for germline testing and its clinical interpretation.

  • An added level of complexity of the clinical interpretation of germline variants exists: variants might reach a threshold of being clinically relevant for therapy but not for risk management.

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Acknowledgements

All authors gratefully acknowledge funding support from the New South Wales (NSW) Office of Health and Medical Research. S.T. acknowledges funding from an Australian Postgraduate Award and a Garvan PhD top-up and Australian Genomics and Health Alliance PhD top-up scholarship (GNT1113531). M.L.B. acknowledges funding from a Cancer Institute NSW Career Development Fellowship (CDF171109). D.M.T. acknowledges funding from an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellowship (APP1104364).

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Affiliations

  1. Cancer Division, Garvan Institute of Medical Research, Sydney, Australia

    • Subotheni Thavaneswaran
    • , Emma Rath
    • , Anthony M. Joshua
    • , Dominique Hess
    • , Mark Pinese
    • , Mandy L. Ballinger
    •  & David M. Thomas
  2. The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, Australia

    • Subotheni Thavaneswaran
    • , Anthony M. Joshua
    •  & David M. Thomas
  3. St Vincent’s Clinical School, University of New South Wales (Medicine), Sydney, Australia

    • Subotheni Thavaneswaran
    • , Anthony M. Joshua
    •  & David M. Thomas
  4. Hereditary Cancer Clinic, Prince of Wales Hospital, Sydney, Australia

    • Kathy Tucker

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Contributions

S.T. researched data for the article. All authors made a substantial contribution to discussions of content. S.T. and D.M.T. wrote the manuscript, and all authors edited and/or reviewed the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Mandy L. Ballinger or David M. Thomas.

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DOI

https://doi.org/10.1038/s41571-019-0179-3