Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan.
Mod Pathol. 2012 Apr;25(4):615-24. doi: 10.1038/modpathol.2011.189. Epub 2011 Dec 9.
ARID1A is a recently identified tumor suppressor gene that is mutated in ∼50% of ovarian clear-cell carcinomas. This mutation is associated with loss of ARID1A protein expression as assessed by immunohistochemistry. The present study aimed at determining the timing of the loss of ARID1A protein expression during the development of ovarian clear-cell carcinoma and assessing its relevance in correlation to PIK3CA gene mutations. A total of 42 clear-cell carcinoma cases with adjacent putative precursor lesions (endometriosis-associated carcinoma cases (n=28) and (clear-cell) adenofibroma-associated carcinoma cases (n=14)) were selected and subjected to immunohistochemical analysis for ARID1A protein expression and direct genomic DNA sequencing of exons 9 and 20 of the PIK3CA gene. ARID1A immunoreactivity was deficient in 17 (61%) of the 28 endometriosis-associated carcinomas and 6 (43%) of the 14 adenofibroma-associated carcinomas. Among the precursor lesions adjacent to the 23 ARID1A-deficient carcinomas, 86% of the non-atypical endometriosis (12 of 14) and 100% of the atypical endometriosis (14 of 14), benign (3 of 3), and borderline (6 of 6) clear-cell adenofibroma components were found to be ARID1A deficient. In contrast, in the 19 patients with ARID1A-intact carcinomas, all of the adjacent precursor lesions retained ARID1A expression regardless of their types and cytological atypia. Analysis of 22 solitary endometrioses and 10 endometrioses distant from ARID1A-deficient carcinomas showed that all of these lesions were diffusely immunoreactive for ARID1A. Among the 42 clear-cell carcinomas, somatic mutations of PIK3CA were detected in 17 (40%) tumors and majority (71%) of these were ARID1A-deficient carcinomas. These results suggest that loss of ARID1A protein expression occurs as a very early event in ovarian clear-cell carcinoma development, similar to the pattern of PIK3CA mutation recently reported by our group, and frequently coexists (not mutually exclusive) with PIK3CA mutations.
ARID1A 是一种最近发现的肿瘤抑制基因，约有 50%的卵巢透明细胞癌发生该基因的突变。免疫组化分析显示，该突变与 ARID1A 蛋白表达缺失相关。本研究旨在确定 ARID1A 蛋白表达缺失在卵巢透明细胞癌发展过程中的时间，并评估其与 PIK3CA 基因突变的相关性。共选择了 42 例透明细胞癌病例及其相邻的潜在前驱病变（子宫内膜异位症相关癌病例 28 例和（透明细胞）腺纤维瘤相关癌病例 14 例），并进行 ARID1A 蛋白表达的免疫组化分析和 PIK3CA 基因外显子 9 和 20 的直接基因组 DNA 测序。28 例子宫内膜异位症相关癌中 17 例（61%）和 14 例腺纤维瘤相关癌中 6 例（43%）存在 ARID1A 免疫反应性缺失。在 23 例 ARID1A 缺陷型癌相邻的前驱病变中，非典型子宫内膜异位症（14 例中的 12 例，86%）、良性（3 例中的 3 例）和交界性（6 例中的 6 例）透明细胞腺纤维瘤成分均存在 ARID1A 缺陷。相比之下，在 19 例 ARID1A 完整型癌患者中，所有相邻的前驱病变均保留 ARID1A 表达，无论其类型和细胞学异型性如何。对 22 例单纯性子宫内膜异位症和 10 例远离 ARID1A 缺陷型癌的子宫内膜异位症进行分析，发现所有这些病变均弥漫性表达 ARID1A。在 42 例透明细胞癌中，检测到 17 例（40%）肿瘤存在 PIK3CA 体细胞突变，其中大多数（71%）为 ARID1A 缺陷型癌。这些结果表明，ARID1A 蛋白表达缺失发生在卵巢透明细胞癌发展的早期，与我们组最近报道的 PIK3CA 突变模式相似，并且常与 PIK3CA 突变共存（非互斥）。
