卵巢透亮細胞癌之分子病理研究

Abstract

AT-rich interactive domain 1A (ARID1A)是switch/sucrose non-fermentable (SWI/SNF)複合體的一個次單元。近年來，ARID1A gene, phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway，以及zinc finger protein 217 (ZNF217) gene被發現是常見於卵巢亮細胞癌的基因變化。E-cadherin表現以及telomerase reverse transcriptase (TERT) promoter突變也可以發生在部份的卵巢亮細胞癌。本研究的目的是找出這些分子基因變化的關連性，以及這些分子基因變化對於臨床預後以及治療的影響。我們發現ARID1A失去表現與年紀較輕、PI3K-Akt pathway變化、以及ZNF217 amplification有關。Chromosome 20q13.2 ZNF217 locus amplification與E-cadherin表現量下降相關。帶有activating PI3k-Akt pathway的卵巢亮細胞癌病人，E-cadherin表現量下降與FIGO stage晚期以及較短的overall survival相關。我們也發現對於早期卵巢亮細胞癌病人(FIGO stage I and II)，TERT promoter突變與較短的disease-free survival和overall survival相關。若早期病人出現復發，帶有TERT promoter突變的病人，通常會於化療後六個月內復發。 我們的結果顯示：ARID1A失去表現與PI3K-Akt pathway活化以及ZNF217 amplification對於卵巢亮細胞癌形成可能有加成的效果。ZNF217可降低E-cadherin的表現，是未來可能的治療標的目標。對於帶有activating PI3K-Akt pathway的卵巢亮細胞癌病人，E-cadherin表現可做為預後因子。對於早期卵巢亮細胞癌的病人，TERT promoter突變是可能的治療標的。

AT-rich interactive domain 1A (ARID1A) is a subunit of switch/sucrose non-fermentable (SWI/SNF) complex. Recently, alterations of ARID1A gene, phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) pathway and zinc finger protein 217 (ZNF217) gene have been identified as frequent molecular genetic changes in ovarian clear cell carcinoma. E-cadherin and mutations of telomerase reverse transcriptase (TERT) promoter were found in some ovarian clear cell carcinomas. The present study was aimed at determining the correlation between these molecular events and other clinicopathological factors, including the prognostic impacts of these clinicopathological factors. We found that loss of ARID1A expression was significantly related to younger patient age, PI3K-Akt pathway activation and ZNF217 amplification. Chromosome 20q13.2 ZNF217 locus amplification was significantly associated with decreased E-cadherin expression. In ovarian clear cell carcinoma patients with activating PI3k-Akt pathway, decreased E-cadherin expression and advanced FIGO stage predicted shorter overall survival. We also found that in ovarian clear cell carcinoma patients with early FIGO stage (stage I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival. In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months. Our results showed that synergic effects of loss of ARID1A and PI3K-Akt pathway activation as well as ZNF217 amplification may be related to the development of ovarian clear cell carcinoma. ZNF217 plays a role in downregulating E-cadherin expression and is a potential therapeutic target for ovarian clear cell carcinoma patients. E-cadherin expression is a prognostic marker for ovarian clear cell carcinoma patients with activating PI3K-Akt pathway. In ovarian clear cell carcinoma of early FIGO stage, TERT promoter mutation is a potential therapeutic target.