Integrated analysis of germline and somatic variants in ovarian cancer

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. McMichael, Matthew A. Wyczalkowski, David E. Larson, Heather K. Schmidt, Christopher A. Miller, Robert S. Fulton, Paul T. Spellman, Elaine R. Mardis, Todd E. Druley, Timothy A. Graubert, Paul J. Goodfellow, Benjamin J. Raphael, Richard K. Wilson and Li Ding ()
Additional contact information
Krishna L. Kanchi: The Genome Institute, Washington University
Kimberly J. Johnson: The Genome Institute, Washington 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
Qunyuan Zhang: The Genome Institute, 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
Heather K. Schmidt: The Genome Institute, Washington University
Christopher A. Miller: The Genome Institute, Washington University
Robert S. Fulton: The Genome Institute, Washington University
Paul T. Spellman: Oregon Health and Science University
Elaine R. Mardis: The Genome Institute, Washington University
Todd E. Druley: Washington University
Timothy A. Graubert: Siteman Cancer Center, 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
Li Ding: The Genome Institute, Washington University

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4156

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