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 Spellman, Elaine R. Mardis, Todd E. Druley, Timothy A. GraubertPaul J. Goodfellow, Benjamin J. Raphael, Richard K. Wilson, Li Ding

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number3156
JournalNature Communications
Volume5
DOIs
StatePublished - Jan 22 2014

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Ovarian Neoplasms
Genes
cancer
Exome
Loss of Heterozygosity
Bioinformatics
Computational Biology
approximation
Carcinoma
genes
annotations
deletion
confidence
magnetic permeability
interactions

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Kanchi, K. L., Johnson, K. J., Lu, C., McLellan, M. D., Leiserson, M. D. M., Wendl, M. C., ... Ding, L. (2014). Integrated analysis of germline and somatic variants in ovarian cancer. Nature Communications, 5, [3156]. https://doi.org/10.1038/ncomms4156

Integrated analysis of germline and somatic variants in ovarian cancer. / Kanchi, Krishna L.; Johnson, Kimberly J.; Lu, Charles; McLellan, Michael D.; Leiserson, Mark D M; Wendl, Michael C.; Zhang, Qunyuan; Koboldt, Daniel C.; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F.; Wyczalkowski, Matthew A.; Larson, David E.; Schmidt, Heather K.; Miller, Christopher A.; Fulton, Robert S.; Spellman, Paul; Mardis, Elaine R.; Druley, Todd E.; Graubert, Timothy A.; Goodfellow, Paul J.; Raphael, Benjamin J.; Wilson, Richard K.; Ding, Li.

In: Nature Communications, Vol. 5, 3156, 22.01.2014.

Research output: Contribution to journalArticle

Kanchi, KL, Johnson, KJ, Lu, C, McLellan, MD, Leiserson, MDM, Wendl, MC, Zhang, Q, Koboldt, DC, Xie, M, Kandoth, C, McMichael, JF, Wyczalkowski, MA, Larson, DE, Schmidt, HK, Miller, CA, Fulton, RS, Spellman, P, Mardis, ER, Druley, TE, Graubert, TA, Goodfellow, PJ, Raphael, BJ, Wilson, RK & Ding, L 2014, 'Integrated analysis of germline and somatic variants in ovarian cancer', Nature Communications, vol. 5, 3156. https://doi.org/10.1038/ncomms4156
Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MDM, Wendl MC et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nature Communications. 2014 Jan 22;5. 3156. https://doi.org/10.1038/ncomms4156
Kanchi, Krishna L. ; Johnson, Kimberly J. ; Lu, Charles ; McLellan, Michael D. ; Leiserson, Mark D M ; Wendl, Michael C. ; Zhang, Qunyuan ; Koboldt, Daniel C. ; Xie, Mingchao ; Kandoth, Cyriac ; McMichael, Joshua F. ; Wyczalkowski, Matthew A. ; Larson, David E. ; Schmidt, Heather K. ; Miller, Christopher A. ; Fulton, Robert S. ; Spellman, Paul ; Mardis, Elaine R. ; Druley, Todd E. ; Graubert, Timothy A. ; Goodfellow, Paul J. ; Raphael, Benjamin J. ; Wilson, Richard K. ; Ding, Li. / Integrated analysis of germline and somatic variants in ovarian cancer. In: Nature Communications. 2014 ; Vol. 5.
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