Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing

透明细胞癌 体细胞 克拉斯 癌症研究 CDKN2A 生物 种系突变 外显子组测序 卵巢癌 癌症 外显子组 癌变 清除单元格 突变 卵巢癌 遗传学 基因
作者
Yusuke Shibuya,Hideki Tokunaga,Sakae Saito,Kazurou Shimokawa,Fumiki Katsuoka,Bin Li,Kaname Kojima,Masao Nagasaki,Masayuki Yamamoto,Nobuo Yaegashi,Jun Yasuda
出处
期刊:Genes, Chromosomes and Cancer [Wiley]
卷期号:57 (2): 51-60 被引量:92
标识
DOI:10.1002/gcc.22507
摘要

Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding noncancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis.
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