Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations and ZNF217 amplification in ovarian clear cell carcinoma

Huang, Haibo; Lin, Ming-Chieh; Huang, Wen Ching; Chiang, Ying‐Cheng; Kuo, Kuan-Ting

doi:10.1038/modpathol.2013.216

Cited by 78 publications

(74 citation statements)

References 34 publications

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“…In previous studies, molecular alterations in ovarian clear cell carcinomas, including ARID1A, PIK3CA, and ZNF217, were either not considered a prognostic factor or signified different conclusions. 22,24,[32][33][34][35][36][37] Our study is the first report on the prognostic impact of TERT promoter mutations in early-stage ovarian clear cell carcinomas. TERT promoter mutations may have a role in the development of chemoresistance, but more in-depth investigations are necessary.…”

Section: Discussionmentioning

confidence: 69%

“…Some cases of ovarian clear cell carcinoma were also reported in our previous study. 22 All patients underwent operations including total hysterectomy with bilateral salpingo-oophorectomy, at least, and no concurrent endometrial and ovarian clear cell carcinomas were found. All patients with ovarian clear cell carcinoma underwent debulking surgery.…”

Section: Patients and Tissue Materialsmentioning

confidence: 99%

“…22 The ARID1A immunoreactivities were divided into either undetectable or positive (weakly or strongly) for nuclear staining, and stromal cells were used as an internal positive control. 24 …”

Section: Immunohistochemistrymentioning

confidence: 99%

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Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

et al. 2015

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Recently, mutations of telomerase reverse transcriptase (TERT) promoter were found in several types of cancer. A few reports demonstrate TERT promoter mutations in ovarian clear cell carcinomas but endometrial clear cell carcinoma has not been studied. The aims of this study were to compare differences of molecular alterations and clinical factors, and identify their prognostic impact in endometrial and ovarian clear cell carcinomas. We evaluated mutations of the TERT promoter and PIK3CA, expression of ARID1A, and other clinicopathological factors in 56 ovarian and 14 endometrial clear cell carcinomas. We found that TERT promoter mutations were present in 21% (3/14) of endometrial clear cell carcinomas and 16% (9/56) of ovarian clear cell carcinomas. Compared with ovarian clear cell carcinomas, endometrial clear cell carcinomas showed older mean patient age (Po0.001), preserved ARID1A immunoreactivity (P ¼ 0.017) and infrequent PIK3CA mutation (P ¼ 0.025). In ovarian clear cell carcinomas, TERT promoter mutations were correlated with patient age 445 (P ¼ 0.045) and preserved ARID1A expression (P ¼ 0.003). In cases of endometrial clear cell carcinoma, TERT promoter mutations were not statistically associated with any other clinicopathological factors. In ovarian clear cell carcinoma patients with early FIGO stage (stages I and II), TERT promoter mutation was an independent prognostic factor and correlated with a shorter disease-free survival and overall survival (P ¼ 0.015 and 0.009, respectively). In recurrent ovarian clear cell carcinoma patients with early FIGO stage, TERT promoter mutations were associated with early relapse within 6 months (P ¼ 0.018). We concluded that TERT promoter mutations were present in endometrial and ovarian clear cell carcinomas. Distinct molecular alteration patterns in endometrial and ovarian clear cell carcinomas implied different processes of tumorigenesis in these morphologically similar tumors. In ovarian clear cell carcinoma of early FIGO stage, patients with TERT promoter mutation require close follow-up during the initial 6 months following chemotherapy. Modern Pathology (2015) 28, 303-311; doi:10.1038/modpathol.2014 published online 1 August 2014 Ovarian clear cell carcinoma represents 5-25% of all epithelial ovarian carcinomas with geographic variation. 1 Compared with high-grade serous adenocarcinomas, ovarian clear cell carcinomas are characterized by a higher incidence among Asians, younger patient age and early tumor staging at presentation, association with endometriosis, higher frequencies of AT-rich interactive domain 1 A (ARID1A) mutation and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation, and higher resistance to first-line platinum and taxane-based chemotherapy.

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Section: Discussionmentioning

confidence: 69%

Section: Patients and Tissue Materialsmentioning

confidence: 99%

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Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

et al. 2015

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“…These results demonstrate that an ARID1A deficit has those three effects on tumor suppression (21). An ARID1A deficit has also been associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, and with the amplification of zinc-finger protein 217 (ZNF217), which are involved in cancer development (24).…”

Section: Chromatin Remodeling-associated Gene Mutations and Carcinogementioning

confidence: 84%

Aberrant chromatin remodeling in gynecological cancer (Review)

et al. 2017

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Abstract. Epigenetic regulatory mechanisms are a current focus in studies investigating cancer. Chromatin remodeling alters chromatin structure and regulates gene expression, and aberrant chromatin remodeling is involved in carcinogenesis. AT-rich interactive domain-containing protein 1A (ARID1A) and SWItch/sucrose non-fermentable-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 are remodeling factors that are mutated in numerous types of cancer. In gynecological cancer, ARID1A mutations have been identified in 46-57% of clear cell carcinoma and 30% of endometrioid carcinoma. Mutations of chromodomain helicase, DNA-binding protein 4 have been detected in 17-21% of endometrial serous cancer, and mutations of ARID1A and mixed-lineage leukemia 3 occur in 36 and 27% of uterine carcinosarcoma, respectively. These data suggest that aberrant chromatin remodeling is a potential cause of cancer, and have led to the development of novel proteins targeting these processes. Additional accumulation of information on the mechanisms of chromatin remodeling and markers for these events may promote personalized anticancer therapies.

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“…Firstly, we identified potential targetable genomic mutations in CCC using an extensive literature search (24,25). Patients with CCC (64%) had ≥1 somatic mutation (24).…”

Section: Candidate Mutated Genes For Enhancing the Therapeutic Ratio mentioning

confidence: 99%

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

et al. 2017

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Abstract. Inhibitors of poly(ADP-ribose) polymerase (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 mutations. Ovarian clear cell cancer (CCC), a subset of ovarian cancer, often appears as low-stage disease with a higher incidence among Japanese. Advanced CCC is highly aggressive with poor patient outcome. The aim of the present study was to determine the potential synthetic lethality gene pairs for PARP inhibitions in patients with CCC through virtual and biological screenings as well as clinical studies. We conducted a literature review for putative PARP sensitivity genes that are associated with the CCC pathophysiology. Previous studies identified a variety of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used as biomarkers or therapeutic targets for PARP inhibition. BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and PTEN were considered as candidate genes for synthetic lethality gene partners for PARP interactions. When considering the biological background underlying PARP inhibition, we hypothesized that PARP inhibitors would be a novel synthetic lethal therapeutic approach for CCC tumors harboring homologous recombination deficiency and activating oncogene mutations. The results showed that the majority of CCC tumors appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of CCC.

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Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations and ZNF217 amplification in ovarian clear cell carcinoma

Cited by 78 publications

References 34 publications

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

Molecular alterations in endometrial and ovarian clear cell carcinomas: clinical impacts of telomerase reverse transcriptase promoter mutation

Aberrant chromatin remodeling in gynecological cancer (Review)

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

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