ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis
ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis
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DOI：
10.1038/s41598-020-71273-7
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发表时间：
2020-08-31
影响因子：
4.6
通讯作者：
Enomoto, Takayuki
中科院分区：
文献类型：
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作者：
Yachida, Nozomi;Yoshihara, Kosuke;Enomoto, Takayuki
ARID1A功能缺失突变伴随ARID1A蛋白表达缺失被认为是子宫内膜异位症相关卵巢癌最重要的驱动因素之一。尽管我们最近的基因组研究表明，在13%的卵巢子宫内膜异位症中检测到ARID1A功能缺失突变，但在卵巢子宫内膜异位症中，ARID1A突变状态与ARID1A蛋白表达之间的关系仍不清楚。对78例卵巢子宫内膜异位症和99例透明细胞癌标本进行ARID1A免疫组织化学染色。我们发现，不仅70例无ARID1A突变的子宫内膜异位症标本，而且8例有ARID1A功能缺失突变的子宫内膜异位症标本都保留了ARID1A蛋白的表达。另一方面，大多数ARID1A功能缺失突变的透明细胞癌显示ARID1A蛋白表达缺失。特别是，含有多个ARID1A功能缺失突变或同时存在单一ARID1A功能缺失突变和ARID1A等位基因失衡的透明细胞癌样本丢失了ARID1A蛋白的表达。然而，ARID1A蛋白在7例ARID1A功能缺失突变的透明细胞癌中仍有表达。这些结果表明，在卵巢子宫内膜异位症和一些透明细胞癌中，单一的ARID1A功能缺失突变不足以导致ARID1A缺失。伴有ARID1A功能缺失突变的卵巢子宫内膜异位症的恶变可能需要进一步的驱动因素。
ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.