Integrated analysis of germline and somatic variants in ovarian cancer.
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.
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2].
Krishna L
KL
Kanchi
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2] Brown School, Washington University, St. Louis, Missouri 63130, USA [3] Oregon Health and Science University, Portland, Oregon 97239, USA [4].
Kimberly J
KJ
Johnson
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2].
Charles
C
Lu
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Michael D
MD
McLellan
Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
Mark D M
MD
Leiserson
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2] Department of Genetics, Washington University, St. Louis, Missouri 63108, USA [3] Department of Mathematics, Washington University, St. Louis, Missouri 63108, USA.
Michael C
MC
Wendl
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2] Department of Genetics, Washington University, St. Louis, Missouri 63108, USA.
Qunyuan
Q
Zhang
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Daniel C
DC
Koboldt
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Mingchao
M
Xie
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Cyriac
C
Kandoth
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Joshua F
JF
McMichael
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Matthew A
MA
Wyczalkowski
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2] Department of Genetics, Washington University, St. Louis, Missouri 63108, USA.
David E
DE
Larson
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Heather K
HK
Schmidt
The Genome Institute, Washington University, St. Louis, Missouri 63108, USA.
Christopher A
CA
Miller
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2] Department of Genetics, Washington University, St. Louis, Missouri 63108, USA.
Robert S
RS
Fulton
Oregon Health and Science University, Portland, Oregon 97239, USA.
Paul T
PT
Spellman
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.
Elaine R
ER
Mardis
1] Department of Genetics, Washington University, St. Louis, Missouri 63108, USA [2] Department of Pediatrics, Washington University, St. Louis, Missouri 63108, USA.
Todd E
TE
Druley
1] Siteman Cancer Center, Washington University, St. Louis, Missouri 63108, USA [2] Department of Medicine, Washington University, St. Louis, Missouri 63108, USA.
Timothy A
TA
Graubert
The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Paul J
PJ
Goodfellow
Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
Benjamin J
BJ
Raphael
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.
Richard K
RK
Wilson
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.
Li
L
Ding
D000368:Aged; D005260:Female; D005854:Germ Cells; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics*