卵巢癌种系和体细胞变异的综合分析
Integrated analysis of germline and somatic variants in ovarian cancer.
作者信息
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 T, Mardis Elaine R, Druley Todd E, Graubert Timothy A, Goodfellow Paul J, Raphael Benjamin J, Wilson Richard K, Ding Li
机构信息
1] The Genome Institute, Washington University, St. Louis, Missouri 63108, USA [2].
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].
出版信息
Nat Commun. 2014;5:3156. doi: 10.1038/ncomms4156.
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.
我们报告了卵巢癌中种系与体细胞联合图谱的首次大规模全外显子组分析。在此，我们分析了429例卵巢癌病例和557例对照的种系和体细胞改变。我们鉴定出3635个高可信度的罕见截短变异和22953个具有预测功能影响的错义变异。我们在20%的病例中发现了范可尼通路基因中的种系截短变异和大片段缺失。在BRCA1、BRCA2和PALB2中显示出罕见截短的富集。此外，我们在以前未与卵巢癌易感性相关的基因（NF1、MAP3K4、CDKN2B和MLL3）中观察到种系截短变异。在分别携带种系BRCA1和BRCA2截短的病例中，100%和76%的病例发现了杂合性缺失的证据。种系与体细胞相互作用分析结合广泛的生物信息学注释鉴定出222个候选功能性种系截短和错义变异，包括两个致病性BRCA1和1个TP53有害变异。最后，种系和体细胞变异的综合分析确定了显著改变的通路，包括范可尼、丝裂原活化蛋白激酶和混合谱系白血病通路。
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