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Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits

Author

Listed:
  • Solip Park

    (The Barcelona Institute of Science and Technology)

  • Fran Supek

    (The Barcelona Institute of Science and Technology
    The Barcelona Institute of Science and Technology
    Rudjer Boskovic Institute
    The Barcelona Institute of Science and Technology)

  • Ben Lehner

    (The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

Abstract

The genetic causes of cancer include both somatic mutations and inherited germline variants. Large-scale tumor sequencing has revolutionized the identification of somatic driver alterations but has had limited impact on the identification of cancer predisposition genes (CPGs). Here we present a statistical method, ALFRED, that tests Knudson’s two-hit hypothesis to systematically identify CPGs from cancer genome data. Applied to ~10,000 tumor exomes the approach identifies known and putative CPGs – including the chromatin modifier NSD1 – that contribute to cancer through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH). Rare germline variants in these genes contribute substantially to cancer risk, including to ~14% of ovarian carcinomas, ~7% of breast tumors, ~4% of uterine corpus endometrial carcinomas, and to a median of 2% of tumors across 17 cancer types.

Suggested Citation

  • Solip Park & Fran Supek & Ben Lehner, 2018. "Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04900-7
    DOI: 10.1038/s41467-018-04900-7
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    Cited by:

    1. Jurica Levatić & Marina Salvadores & Francisco Fuster-Tormo & Fran Supek, 2022. "Mutational signatures are markers of drug sensitivity of cancer cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Solip Park & Fran Supek & Ben Lehner, 2021. "Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Elizaveta Besedina & Fran Supek, 2024. "Copy number losses of oncogenes and gains of tumor suppressor genes generate common driver mutations," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Mischan Vali-Pour & Solip Park & Jose Espinosa-Carrasco & Daniel Ortiz-Martínez & Ben Lehner & Fran Supek, 2022. "The impact of rare germline variants on human somatic mutation processes," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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