ARID1A mutations in endometriosis-associated ovarian carcinomas.
ARID1A mutations in endometriosis-associated ovarian carcinomas.
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DOI：
10.1056/nejmoa1008433
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发表时间：
2010-10-14
期刊：
影响因子：
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通讯作者：
Huntsman DG
中科院分区：
文献类型：
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作者：
Wiegand KC;Shah SP;Al-Agha OM;Zhao Y;Tse K;Zeng T;Senz J;McConechy MK;Anglesio MS;Kalloger SE;Yang W;Heravi-Moussavi A;Giuliany R;Chow C;Fee J;Zayed A;Prentice L;Melnyk N;Turashvili G;Delaney AD;Madore J;Yip S;McPherson AW;Ha G;Bell L;Fereday S;Tam A;Galletta L;Tonin PN;Provencher D;Miller D;Jones SJ;Moore RA;Morin GB;Oloumi A;Boyd N;Aparicio SA;Shih IeM;Mes-Masson AM;Bowtell DD;Hirst M;Gilks B;Marra MA;Huntsman DG
卵巢透明细胞癌和子宫内膜样癌可能由子宫内膜异位症引起，但这种转化所涉及的分子事件尚未被描述。我们对18例卵巢透明细胞癌和1例卵巢透明细胞癌细胞系的全部转录本进行了测序，并在其中6个样本中发现了ARID1A(富含AT的相互作用域1A[SWI-like]基因)的体细胞突变。ARID1A编码BAF250a，BAF250a是SWI-SNF染色质重塑复合体的关键成分。我们对另外210例卵巢癌和第二株卵巢透明细胞癌细胞系中的ARID1A进行了测序，并通过免疫组织化学方法检测了另外455例卵巢癌中BAF250a的表达。在119例卵巢透明细胞癌中55例(46%)，33例子宫内膜样癌中10例(30%)，在76例高级别浆液性卵巢癌中均未发现ARID1A突变。17例癌症各有两个体细胞突变。BAF250a蛋白的缺失与卵巢透明细胞癌和子宫内膜样癌亚型以及ARID1A突变的存在密切相关。在2例患者中，ARID1A突变和BAF250a表达缺失在肿瘤和毗邻的不典型子宫内膜异位症中明显存在，而在远处的子宫内膜异位症病变中则不明显。这些数据表明，ARID1A是一种肿瘤抑制基因，在卵巢透明细胞癌和子宫内膜样癌中经常被破坏。由于在癌前病变中可以看到ARID1A突变和BAF250a的丢失，我们推测这是子宫内膜异位症向癌转化的早期事件。(由不列颠哥伦比亚省癌症基金会和温哥华总医院-不列颠哥伦比亚大学医院基金会资助。)
Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian clear-cell carcinoma and endometrioid carcinoma subtypes and the presence of ARID1A mutations. In two patients, ARID1A mutations and loss of BAF250a expression were evident in the tumor and contiguous atypical endometriosis but not in distant endometriotic lesions. These data implicate ARID1A as a tumor-suppressor gene frequently disrupted in ovarian clear-cell and endometrioid carcinomas. Since ARID1A mutation and loss of BAF250a can be seen in the preneoplastic lesions, we speculate that this is an early event in the transformation of endometriosis into cancer. (Funded by the British Columbia Cancer Foundation and the Vancouver General Hospital–University of British Columbia Hospital Foundation.)