Journal Article

Integrated analysis of germline and somatic variants in ovarian cancer

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

2014

Overview

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. Ovarian cancer is one of the most common cancers in women and has an average 5-year survival of only 43%. Here, Kanchi et al. describe the germline and somatic mutation spectrum in ovarian cancer patients and identify potential risk variants associated with the disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 631/208/68 / 631/67/1517/1709 / Aged / Bioinformatics / Breast cancer / Female / Germ Cells / Humanities and Social Sciences / Humans / Loss of Heterozygosity / Middle Aged / multidisciplinary / Oncogenes / Ovarian cancer / Ovarian Neoplasms - genetics / Science / Science (multidisciplinary)