Integrated analysis of germline and somatic variants in ovarian cancer.

Nat Commun 2014 ;5:3156

1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2] Department of Genetics, Washington University, St. Louis, Missouri 63108, USA [3] Siteman Cancer Center, Washington University, St. Louis, Missouri 63108, USA [4] Department of Medicine, Washington University, St. Louis, Missouri 63108, USA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms4156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025965PMC
March 2016
52 Reads

Publication Analysis

Top Keywords

germline somatic
12
ovarian cancer
12
germline truncation
12
analysis combined
8
missense variants
8
brca1 brca2
8
somatic variants
8
truncation variants
8
germline
7
variants
7
bioinformatics annotation
4
fanconi pathway
4
extensive bioinformatics
4
combined extensive
4
deletions fanconi
4
truncation missense
4
20% cases
4
genes 20%
4
interaction analysis
4
pathway genes
4

Similar Publications