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Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

Author

Listed:
  • Tao Qing

    (Yale University)

  • Hussein Mohsen

    (Yale University)

  • Michal Marczyk

    (Yale University
    Silesian University of Technology)

  • Yixuan Ye

    (Yale University)

  • Tess O’Meara

    (Yale University)

  • Hongyu Zhao

    (Yale University
    Yale University)

  • Jeffrey P. Townsend

    (Yale University
    Yale University)

  • Mark Gerstein

    (Yale University
    Yale University
    Yale University
    Yale University)

  • Christos Hatzis

    (Yale University
    Bristol-Myers Squibb)

  • Yuval Kluger

    (Yale University
    Yale University
    Yale University)

  • Lajos Pusztai

    (Yale University)

Abstract

Cancers harbor many somatic mutations and germline variants, we hypothesized that the combined effect of germline variants that alter the structure, expression, or function of protein-coding regions of cancer-biology related genes (gHFI) determines which and how many somatic mutations (sM) must occur for malignant transformation. We show that gHFI and sM affect overlapping genes and the average number of gHFI in cancer hallmark genes is higher in patients who develop cancer at a younger age (r = −0.77, P = 0.0051), while the average number of sM increases in increasing age groups (r = 0.92, P = 0.000073). A strong negative correlation exists between average gHFI and average sM burden in increasing age groups (r = −0.70, P = 0.017). In early-onset cancers, the larger gHFI burden in cancer genes suggests a greater contribution of germline alterations to the transformation process while late-onset cancers are more driven by somatic mutations.

Suggested Citation

  • Tao Qing & Hussein Mohsen & Michal Marczyk & Yixuan Ye & Tess O’Meara & Hongyu Zhao & Jeffrey P. Townsend & Mark Gerstein & Christos Hatzis & Yuval Kluger & Lajos Pusztai, 2020. "Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16293-7
    DOI: 10.1038/s41467-020-16293-7
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    Cited by:

    1. Ashley T. Sendell-Price & Frank J. Tulenko & Mats Pettersson & Du Kang & Margo Montandon & Sylke Winkler & Kathleen Kulb & Gavin P. Naylor & Adam Phillippy & Olivier Fedrigo & Jacquelyn Mountcastle & , 2023. "Low mutation rate in epaulette sharks is consistent with a slow rate of evolution in sharks," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Eun Seop Seo & Ji Won Lee & Jinyeong Lim & Sunghwan Shin & Hee Won Cho & Hee Young Ju & Keon Hee Yoo & Ki Woong Sung & Woong-Yang Park, 2024. "Germline functional variants contribute to somatic mutation and outcomes in neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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