TY - JOUR
T1 - Integrated analysis of germline and somatic variants in ovarian cancer
AU - Kanchi, Krishna L.
AU - Johnson, Kimberly J.
AU - Lu, Charles
AU - McLellan, Michael D.
AU - Leiserson, Mark D.M.
AU - Wendl, Michael C.
AU - Zhang, Qunyuan
AU - Koboldt, Daniel C.
AU - Xie, Mingchao
AU - Kandoth, Cyriac
AU - McMichael, Joshua F.
AU - Wyczalkowski, Matthew A.
AU - Larson, David E.
AU - Schmidt, Heather K.
AU - Miller, Christopher A.
AU - Fulton, Robert S.
AU - Spellman, Paul T.
AU - Mardis, Elaine R.
AU - Druley, Todd E.
AU - Graubert, Timothy A.
AU - Goodfellow, Paul J.
AU - Raphael, Benjamin J.
AU - Wilson, Richard K.
AU - Ding, Li
N1 - Funding Information:
This work was supported by the National Cancer Institute Grant R01CA180006 to L.D. and National Human Genome Research Institute Grants R01HG005690 to B.J.R. and U54HG003079 to R.K.W.
PY - 2014/1/22
Y1 - 2014/1/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892968131&partnerID=8YFLogxK
U2 - 10.1038/ncomms4156
DO - 10.1038/ncomms4156
M3 - Article
C2 - 24448499
AN - SCOPUS:84892968131
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 3156
ER -