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.