In the present study, we investigated the prognostic significance of clinicopathological factors in patients with OCCC treated at our institution over a period of 23 years. We observed that the rates of ARID1A loss expression and somatic driver mutations of PIK3CA and TERTp to be 54% (70/129), 56% (61/109) and 26% (23/87), respectively. A large-scale sequencing of putative somatic driver mutations in 401 OCCC tumors showed that the mutation of the PIK3CA and TERTp genes were 49% and 20%, which were slightly lower than ours.(Bolton et al., 2022) In general, TERTp mutations correlate with increased TERT mRNA levels and increased telomerase activity.(Roake & Artandi, 2020) The primary TERT promoter (TERTp) mutations occur at positions 1,295,228 (-124 C > T) and 1,295,250 (-146 C > T).(Hafezi & Perez Bercoff, 2020) Consistent with previous studies, the − 124 C > T mutation predominated among TERTp mutations with a mutation rate of 21.8%. (Boscolo-Rizzo, Tirelli et al., 2023, Giunco, Boscolo-Rizzo et al., 2021, Giunco, Padovan et al., 2023, Huang et al., 2015, Liu, Bishop et al., 2013, Nishikimi, Nakagawa et al., 2018, Spiegl-Kreinecker, Lotsch et al., 2015) The − 124 C > T mutation and stage were independent prognostic factor for OS in our cohort. Patients with the − 124 C > T mutation showed significantly longer PFS and OS than wild-type patients, and more likely to have a normal preoperative serum CA125 level, had a higher prevalence of SNP and less likely to relapse.
Compared to other histological types of ovarian cancer, clear cell carcinomas have longer mean relative telomere lengths, and longer telomeres are associated with increased mortality.(Kuhn, Meeker et al., 2011) Ovarian clear cell carcinoma cell lines with the − 124C > T mutation in the TERT promoter (TERTp) demonstrated elevated TERT mRNA expression compared to cell lines without the TERTp mutation. (Wu, Ayhan et al., 2014) Another study reported that the TERTp hotspot mutations (-124C > T and − 146C > T) had a higher promoter activity than the wild-type, and the promoter activity of the uncommon site mutations was the lowest. (Kobayashi, Nishikimi et al., 2023) Furthermore, TERT expression increased with tumor grade and stage. (Maraei, Hatta et al., 2012) However, the impact of TERTp mutations on patient outcomes in OCCC remains unclear. Huang et al found that TERTp mutation was an independent prognostic factor that correlated with shorter disease-free survival (DFS) and overall survival in early-stage patients.(Huang et al., 2015) Recently, Yoo et al demonstrated that TERTp mutations had significant prognostic value in predicting tumor recurrence, platinum resistance, and DFS in patients with OCCC.(Yoo H, 2023) A similar conclusion from Irshaid et al reported that a TERTp mutation could be further stratified as high-risk OCCC in the no specific molecular profile subgroup.(Irshaid, Costigan et al., 2023) In contrast to the above research, Kobayashi et al reported that the progression-free survival rate of the “enhancer-type” group including the hotspot mutations of TERTp was significantly longer than that of the wild-type and “suppressor-type” (with uncommon mutations) mutation groups.(Kobayashi et al., 2023) While no significant difference in disease-specific overall survival was observed between patients with and without TERTp hotspot mutations in the cohorts of Nishikimi et al and Wu et al.(Nishikimi et al., 2018, Wu et al., 2014) In our study, patients with the − 124C > T mutation had longer PFS and OS than those with wild-type. We further analyzed the correlation between the two different hotspot mutations and prognosis. In addition, we have a longer observation period. This favorable prognosis associated with TERTp has also been demonstrated in some subgroups of medulloblastoma, glioma and melanoma. (Blateau, Coyaud et al., 2020, Remke, Ramaswamy et al., 2013, Yang, Cai et al., 2016)
The prognostic and predictive role of TERTp mutations is complex, and may be related to tumor heterogeneity and diverse molecular backgrounds. The effect of the TERTp mutations on survival might be modified by a SNP at the mutation sites. The variant allele of the rs2853669 polymorphism decreased promoter activity in the presence of TERTp mutations, especially in the cases with − 124 C > T mutation, ultimately improving patients’ prognosis.(Rachakonda, Hosen et al., 2013) In our study, the − 124 C > T mutation was mainly accompanied by SNP. TERTp mutations might increase tumor immunogenicity. Analysis of pan-cancer cell lines revealed an expression signature of TERTp mutation dominated by epithelial-to-mesenchymal transition (EMT) and MAPK signaling.(Stern, Hibshman et al., 2020) In lung cancer, high EMT scores were associated with the increased expression of immune checkpoints.(Mak, Tong et al., 2016) Patients harboring TERTp mutations tended to show increased PD-L1 expression in glioma.(Holzl, Hutarew et al., 2021) Additional confounding factors such as MGMT promoter methylation, may influence patient survival in association with TERTp mutation status. Methylation of MGMT promoter significantly increased the PFS and OS of the patients with TERTp mutations in glioblastoma.(Arita, Yamasaki et al., 2016) Furthermore, the different prognosis between the − 124 C > T and − 146 C > T mutation may be attributed to different functions.(Li, Zhou et al., 2015) Further research is needed to be done to understand how TERTp mutations affect patient prognosis.
ARID1A encodes an accessory subunit of the SWI/SNF chromatin remodeling complex, which exhibited a high frequency of mutations in OCCC.(Fukumoto, Magno et al., 2018) In a comprehensive study involving 1,432 patients with endometrium-related gynecological cancers, loss of ARID1A expression predicted shorter progression free survival.(Katagiri et al., 2012, Liu, Xu et al., 2017) Studies have demonstrated that ARID1A directly represses HDAC6 gene transcription, and mutations in ARID1A and TP53 are mutually exclusive.(Bitler, Wu et al., 2017, Guan, Wang et al., 2011) Additionally, high HDAC6 expression had an adverse effect on the PFS in patients with ARID1A loss.(Yano et al., 2019) Futhermore, PIK3CA mutations were significantly associated with a favorable overall survival in a cohort of 56 Japanese patients with OCCC.(Rahman et al., 2012) Huang et al reported a significant correlation between loss of ARID1A expression and PI3K-Akt signaling pathway activation.(Huang, Lin et al., 2014) In previous studies, TERTp mutations with loss of ARID1A expression or PIK3CA mutations in OCCC were mutually exclusive.(Huang et al., 2015, Wu et al., 2014) Cyclin E1 is a highly conserved cell cycle regulation protein, and its overexpression is closely correlated with TERTp mutations and poor outcomes in stage I patients.(Ayhan et al., 2017) However, these associations were not found in our study with larger samples.
In conclusion, we assessed the prognostic value of common gene mutations and clinicopathological factors in OCCC and found that the − 124 C > T mutation of TERTp represented a favorable prognostic factor for OS in OCCC. However, further studies are required to elucidate the molecular mechanisms by which TERTp mutation affect the prognosis of patients with OCCC.