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Integrated analysis of germline and somatic variants in ovarian cancer

Author

Listed:
  • Krishna L. Kanchi

    (The Genome Institute, Washington University)

  • Kimberly J. Johnson

    (The Genome Institute, Washington University
    Brown School, Washington University
    Oregon Health and Science University)

  • Charles Lu

    (The Genome Institute, Washington University)

  • Michael D. McLellan

    (The Genome Institute, Washington University)

  • Mark D. M. Leiserson

    (Brown University)

  • Michael C. Wendl

    (The Genome Institute, Washington University
    Washington University
    Washington University)

  • Qunyuan Zhang

    (The Genome Institute, Washington University
    Washington University)

  • Daniel C. Koboldt

    (The Genome Institute, Washington University)

  • Mingchao Xie

    (The Genome Institute, Washington University)

  • Cyriac Kandoth

    (The Genome Institute, Washington University)

  • Joshua F. McMichael

    (The Genome Institute, Washington University)

  • Matthew A. Wyczalkowski

    (The Genome Institute, Washington University)

  • David E. Larson

    (The Genome Institute, Washington University
    Washington University)

  • Heather K. Schmidt

    (The Genome Institute, Washington University)

  • Christopher A. Miller

    (The Genome Institute, Washington University)

  • Robert S. Fulton

    (The Genome Institute, Washington University
    Washington University)

  • Paul T. Spellman

    (Oregon Health and Science University)

  • Elaine R. Mardis

    (The Genome Institute, Washington University
    Washington University
    Siteman Cancer Center, Washington University)

  • Todd E. Druley

    (Washington University
    Washington University)

  • Timothy A. Graubert

    (Siteman Cancer Center, Washington University
    Washington University)

  • Paul J. Goodfellow

    (The Ohio State University Comprehensive Cancer Center, The Ohio State University)

  • Benjamin J. Raphael

    (Brown University)

  • Richard K. Wilson

    (The Genome Institute, Washington University
    Washington University
    Siteman Cancer Center, Washington University)

  • Li Ding

    (The Genome Institute, Washington University
    Washington University
    Siteman Cancer Center, Washington University
    Washington University)

Abstract

We report the first large-scale exome-wide analysis of the combined germline–somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline–somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

Suggested Citation

  • Krishna L. Kanchi & Kimberly J. Johnson & Charles Lu & Michael D. McLellan & Mark D. M. Leiserson & Michael C. Wendl & Qunyuan Zhang & Daniel C. Koboldt & Mingchao Xie & Cyriac Kandoth & Joshua F. McM, 2014. "Integrated analysis of germline and somatic variants in ovarian cancer," Nature Communications, Nature, vol. 5(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4156
    DOI: 10.1038/ncomms4156
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