Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.
Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer.
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DOI：
10.1101/gr.137596.112
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发表时间：
2012-11
期刊：
影响因子：
7
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Liang H;Cheung LW;Li J;Ju Z;Yu S;Stemke-Hale K;Dogruluk T;Lu Y;Liu X;Gu C;Guo W;Scherer SE;Carter H;Westin SN;Dyer MD;Verhaak RG;Zhang F;Karchin R;Liu CG;Lu KH;Broaddus RR;Scott KL;Hennessy BT;Mills GB
Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the “sensor” cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Kaneda, H.;Arao, T.;Matsumoto, K.;De Velasco, M. A.;Tamura, D.;Aomatsu, K.;Kudo, K.;Sakai, K.;Nagai, T.;Fujita, Y.;Tanaka, K.;Yanagihara, K.;Yamada, Y.;Okamoto, I.;Nakagawa, K.;Nishio, K.
通讯作者：
Nishio, K.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
11.5
作者：
Jia, Lin;Liu, Yongjuan;Zheng, Wenxin
通讯作者：
Zheng, Wenxin
影响因子：
3.6
作者：
Carter, Hannah;Samayoa, Josue;Karchin, Rachel
通讯作者：
Karchin, Rachel