Gene amplification of chromatin remodeling factor SMARCC2 and low protein expression of ACTL6A are unfavorable factors in ovarian high‑grade serous carcinoma

Abstract

Ovarian high-grade serous carcinoma (OHGSC) is the most common type of ovarian cancer worldwide. Genome sequencing has identified mutations in chromatin remodeling factors (CRFs) in gynecological cancer, such as clear cell carcinoma, endometrioid carcinoma and endometrial serous carcinoma. However, to the best of our knowledge, the association between CRFs and OHGSC remains unexplored. The present study aimed to investigate the clinicopathological and molecular characteristics of CRF dysfunction in OHGSC. CRF alterations were analyzed through numerous methods, including the analysis of public next-generation sequencing (NGS) data from 585 ovarian serous carcinoma cases from The Cancer Genome Atlas (TCGA), immunohistochemistry (IHC), and DNA copy number assays, which were performed on 203 surgically resected OHGSC samples. In the public NGS dataset, the most frequent genetic alteration was actin-like protein 6A (ACTL6A) amplification at 19.5%. Switch/sucrose non-fermentable related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 (SMARCC2) amplification (3.1%) was associated with significantly decreased overall survival (OS). In addition, chromodomain-helicase-DNA-binding protein 4 (CHD4) amplification (5.7%) exhibited unfavorable outcome trends, although not statistically significant. IHC revealed the protein expression loss of ARID1A (2.5%), SMARCA2 (2.5%) and SMARCA4 (3.9%). The protein expression levels of ACTL6A, SMARCC2 and CHD4 were evaluated using H-score. Patients with low protein expression levels of ACTL6A showed a significantly decreased OS. Copy number gain or gene amplification was demonstrated in ACTL6A (66.2%) and SMARCC2 (33.5%), while shallow deletion or deep deletion was demonstrated in CHD4 (70.7%). However, there was no statistically significant difference in protein levels of these CRFs, between the different copy number alterations (CNAs). Overall, OHGSC exhibited CNAs and protein loss, indicating possible gene alterations in CRFs. Moreover, there was a significant association between the protein expression levels of ACTL6A and poor prognosis. Based on these findings, it is suggested that CRFs could serve as prognostic markers for OHGSC.