Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing
Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing
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应用下一代测序技术检测卵巢透明细胞癌的体细胞遗传学改变
DOI：
10.1002/gcc.22507
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发表时间：
2018-02-01
影响因子：
3.7
通讯作者：
Yasuda, Jun
中科院分区：
文献类型：
--
作者：
Shibuya, Yusuke;Tokunaga, Hideki;Yasuda, Jun
卵巢透明细胞癌（OCCC）是卵巢癌中最难治的亚型，在日本人中比高加索人更常见（分别占所有卵巢癌的25%和5%）。本研究的目的是发现可能导致OCCC的基因组改变和有效的化疗分子靶点。从2007年至2015年在东北大学医院收集的福尔马林固定的石蜡包埋标本中提取了48例OCCC组织和相应非癌组织的配对基因组DNA。所有标本进行外显子组测序和体细胞遗传变异进行了鉴定。我们根据突变谱将病例分为三类。临床特征，如发病年龄和子宫内膜异位症是相似的集群之间，但一个集群显示与APOBEC激活相关的突变，表明其对OCCC病例的子集的贡献。有3例高度突变病例（显示出比其他45例病例高12倍或更高的体细胞突变），并且它们具有种系和体细胞错配修复基因改变。常见的突变基因是ARID1A（66.7%）、PIK3CA（50%）、PPP2R1A（18.8%）和KRAS（16.7%）。在27.1%的OCCC病例中发现了对化疗药物选择重要的体细胞突变，如BRAF、ERBB2、PDGFRB、PGR和KRAS，表明外显子组分析对OCCC的临床重要性。我们的研究表明，错配修复缺陷或APOBEC激活引起的遗传不稳定性在OCCC癌变过程中起关键作用。
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.