Abstract
Background/Aim: A small subset of patients with ovarian clear cell carcinoma (OCCC) harbors telomerase reverse transcriptase promoter (TERTp) mutations. We aimed to analyze the clinicopathological and molecular characteristics of TERTp-mutant OCCC and investigate whether TERTp mutations are associated with the clinicopathological characteristics and outcomes of patients with OCCC. Patients and Methods: We included 11 OCCC cases in our study. Targeted sequencing was performed with a thorough review of pathology slides and electronic medical records. Results: Eleven OCCCs harbored two hotspot TERTp mutations: c.1-146C>T (6/11) and c.1-124C>T (5/11). All patients (11/11) who underwent postoperative adjuvant chemotherapy experienced tumor recurrence, and eight of them were classified as platinum-resistant. TERTp-mutant OCCC showed significantly higher frequencies of postoperative recurrence and relapse within six months of chemotherapy. TERTp mutations significantly predicted disease-free survival (DFS) in patients with OCCC. Conclusion: We demonstrate that TERTp mutations have significant prognostic value for predicting tumor recurrence, platinum resistance, and worse DFS in patients with OCCC.
- Ovarian clear cell carcinoma
- telomerase reverse transcriptase
- promoter mutation
- recurrence
- platinum resistance
- survival
Telomerase is a ribonucleotide protein complex, whose most important subunits are the telomerase reverse transcriptase (TERT), a protein with a reverse transcriptase function, and the telomerase RNA component, an RNA that serves as a template for telomeres (1). Under normal conditions, telomerase repression or telomere shortening plays a role in preventing the dysregulation of cellular proliferation. In telomerase deficiency, DNA polymerase eventually leads to telomere shortening. If the telomere length is shortened beyond a certain extent, the telomere can no longer function normally. The DNA damage response pathway is then activated, and cells enter the process of growth arrest (2-4). This process of replicative senescence prevents tumor occurrence by blocking gene mutations or cellular proliferation (5). Because the signature of carcinoma cells is immortality, it is necessary for them to surpass senescence during oncogenesis. This goal can be achieved through telomerase activation (5).
The human TERT gene is located on chromosome 5 with the core promoter lying 181-base pair (bp) upstream of the transcription initiation site (5). Many types of human carcinomas are caused by promoter mutations that can change the binding site of a transcription factor that normally binds to increase transcription. Two known hotspots of TERT promoter (TERTp) mutations are c.1-146C>T (p.C250T) and c.1-124C>T (p.C228T) (5). These mutations create binding motifs for transcription factors, such as the E26 transformation-specific transcription factor/ternary complex factor, which increases TERTp activity by up to four-fold (6). Hotspot mutations of TERTp contribute to the pathogenesis of malignant melanoma, glioma, breast cancer, prostate cancer, thyroid cancer, and ovarian carcinoma (7).
Ovarian clear cell carcinoma (OCCC) is the second most common histological type of ovarian carcinoma after high-grade serous carcinoma (HGSC), accounting for 5-11% of all ovarian carcinoma cases (8). OCCC is a distinct pathological entity, and its clinical and morphological features distinguish it from other types of ovarian carcinoma. OCCC usually presents as a large, solid, unilateral cystic mass in the pelvic cavity. This tumor is characterized by hobnail or cuboidal cells with uniform nuclear atypia and prominent nucleoli, lining hyalinized papillae or protruding into the lumina of the tubulocystic structure (9). The incidence of OCCC varies greatly according to race and region, with a higher relative prevalence in Asian populations. This tumor is more common in Japanese (15-25%) and Taiwanese (19%) populations than in North Americans or Europeans (1-12%) (10). OCCC is associated with endometriosis and is more often diagnosed at an early stage in young women than is HGSC. Patients with early stage OCCC have a relatively favorable prognosis (11).
Recently, we have encountered several cases of OCCC harboring TERTp mutations. Most patients develop posttreatment recurrences and resistance to platinum-based combination chemotherapy. Recent studies have documented that OCCCs harboring TERTp mutations have worse prognosis than those without (7). This study aimed to clarify the clinicopathological and prognostic significance of TERTp mutations in patients with OCCC. We analyzed the clinical features and pathological characteristics of TERTp-mutant OCCC and investigated whether TERTp mutations were associated with the clinicopathological characteristics and outcomes of patients with OCCC.
Patients and Methods
Case selection. This study (2023-06-029) was approved by the Institutional Review Board of the Samsung Medical Center (Seoul, Republic of Korea). A pathology database was searched for malignant ovarian lesions harboring TERTp mutations. Between February 2018 and August 2021, we identified 18 cases of primary and metastatic ovarian malignancies (Table I), including OCCC (11 cases), HGSC (3 cases), endometrioid carcinoma (EC; 2 cases), adult granulosa cell tumor (AGCT; 1 case), and adenosarcoma with sarcomatous overgrowth (AS-SO; 1 case). All the patients underwent primary debulking surgery. None of the patients underwent preoperative neoadjuvant chemotherapy.
Ovarian malignancies harboring telomerase reverse transcriptase promoter (TERTp) mutations.
Clinicopathological data collection. The following clinical and pathological information was obtained from the electronic medical records and pathology reports of 11 patients with OCCC: age of patients at initial diagnosis, initial International Federation of Gynecology and Obstetrics (FIGO) stage (12), residual tumor size after primary debulking surgery, post-operative treatment, post-operative recurrence, platinum-resistant recurrence, AT-rich interaction domain 1A (ARID1A) mutation, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, post-operative disease-free survival (DFS), survival status, post-operative overall survival (OS), and initial interpretation of MMR protein results. For each case, the most representative block containing the highest proportion of viable tumour (at least 80% of total tissue area) was selected to perform next-generation sequencing.
Next-generation sequencing. For DNA extraction, five slices of 5 μm-thick formalin-fixed, paraffin-embedded tissue were obtained from the most representative block. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissues using a Qiagen DNA FFPE Tissue Kit (Qiagen, Valencia, CA, USA). The DNA yield was evaluated using a Nanodrop 8000 Spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA) and Qubit 3.0 Fluorometer (Thermo Fisher Scientific). DNA size was examined using 2200 TapeStation Software (Agilent Technologies, Santa Clara, CA, USA). Specimens with a DNA yield of >100 ng and a median DNA fragment size of at least 350 bp were selected for targeted sequencing. Targeted sequencing was performed using CancerSCAN (Samsung Genomic Institute, Samsung Medical Center) (13-15), which included whole exomes of 375 carcinoma-related genes and intronic regions of 23 genes. The genomic DNA was sheared using a Covaris S220 Focused-ultrasonicator (Covaris, Woburn, MA, USA). Target capture was performed using a SureSelect XT Reagent Kit and HSQ (Agilent Technologies), and a paired-end sequencing library was constructed using a barcode. Sequencing was performed using the 100-bp paired-end mode of the TruSeq Rapid PE Cluster Kit and TruSeq Rapid SBS Kit on a HiSeq 2500 System (Illumina, San Diego, CA, USA). The paired-end reads were aligned to the human reference genome (hg19) using the Burrows-Wheeler Aligner-maximal exact match v0.7.5. Samtools v0.1.18, Genome Analysis Tool Kit v3.1-1, and Picard v1.93 were used for binary alignment map file handling, local realignment, and the removal of duplicate reads, respectively. Samples with a mean target coverage of less than 200× were excluded from further analysis. Single nucleotide variants with a variant allele frequency of >1% were detected using MuTect v1.1.4, Lowfreq v0.6.1. Sequencing errors were filtered using an in-house algorithm with data extracted from each binary alignment map file. Insertions and deletions (indels) less than 30 bp in size were detected using Pindel v0.2.5a4. Possible germline polymorphisms were also filtered out if the variant allele frequency was >0.1% in any of the normal population databases, including the 1000 Genomes Project; Exome Aggregation Consortium; National Heart, Lung, and Blood Exome Sequencing Project; Korean Reference Genome; and Korean Variant Archive. Structural variants and large indels (>30 bp) were detected using an in-house structural variant caller (16, 17). Copy number alterations of each gene were also detected using an in-house copy number caller with copy numbers >6 marked as amplifications and copy numbers <0.7 designated as deletions (16, 17).
Statistical analysis. Whether there were significant differences in clinicopathological characteristics according to TERTp mutational status in patients with OCCC was determined using the independent two-sample t-test, Pearson’s chi-squared test, Fisher’s exact test, or linear-by-linear association test. The prognostic significance of TERTp mutational status in patients with OCCC was investigated by conducting univariate survival analyses. Curves for DFS and OS were drawn using the Kaplan-Meier method, and differences between the curves were analyzed using the log-rank test for univariate survival analysis. All statistical analyses were performed using IBM SPSS Statistics for Windows, v23.0 (IBM Corporation, Armonk, NY, USA). Mutational mapping was performed using RStudio and R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was defined as p<0.05.
Results
TERTp mutation in various histological types of ovarian malignancies. Table I and Figure 1 summarize the pathological and genetic features of the 18 ovarian malignancies harboring TERTp mutations. Fourteen and four tissue samples were obtained from the primary and metastatic ovarian malignancies, respectively. Metastatic tumors were resected from the mesentery (2/18), rectum (1/18), and diaphragmatic peritoneum (1/18). Two known hotspot mutations, c.1-124C>T (8/18; 44.4%) and c.1-146C>T (7/18; 38.9%), were more common than c.1-245T>C (2/18; 00.0%) and c.1-138/-139CC>TT (1/18; 5.6%). The variant allele frequencies ranged from 4.6% to 93.8%. OCCCs harbored either c.1-146C>T (6/11; 54.5%) or c.1-124C>T (5/11; 45.5%). Two ECs and AS-SO harbored c.1-124C>T, and AGCT harbored c.1-146C>T. In contrast, three HGSCs had uncommon TERTp mutations, including c.1-245T>C (2/3; 66.7%) and c.1-138/-139CC>TT (1/3; 33.3%). Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) were detected in four OCCCs, one EC, and one AS-SO. Mutations in truncated AT-rich interactive domain 1A (ARID1A) were identified in four OCCCs. Pathogenic tumor protein 53 (TP53) mutations were detected in three HGSCs and one OCCC. Other genes showing pathogenic mutations included neurogenic locus Notch homolog protein 1 (NOTCH1; 2/18), E-cadherin (CDH1; 1/18), ataxia-telangiectasia mutated (ATM; 1/18), protein polybromo-1 (PRBM1; 2/18), erb-b2 receptor tyrosine kinase 2 (ERBB2; 2/18), c-mesenchymal-epithelial transition factor proto-oncogene, receptor tyrosine kinase (MET; 1/18), tet methylcytosine dioxygenase 2 (TET2; 1/18), and forkhead box L2 (FOXL2; 1/18). Five of the eight patients (62.5%) harboring c.124C>T mutations also had PIK3CA mutations, whereas only one of the seven patients (14.3%) with c.1-146C>T mutations had PIK3CA mutations. Conversely, ARID1A mutations were detected in three c.1-146C>T-mutant cases (42.9%), but only in one c.1-124C>T-mutant case (12.5%). Among the four OCCCs, TERTp mutation was the only mutation detected.
Results of targeted sequencing analyses of various ovarian malignancies. Regarding telomerase reverse transcriptase promoter (TERTp) mutations, all ovarian clear cell carcinoma (CCC) cases harbor one of the two hotspot mutations, including c.1-146C>T and c.1-124C>T. In contrast, three high-grade serous carcinoma (HGSC) cases harbor uncommon TERTp mutations, including c.1-245T>C and c.1-138/-139CC>TT. Some OCCC cases also harbor mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and AT-rich interactive domain 1A (ARID1A). Pathogenic tumor protein 53 (TP53) mutations are detected in one OCCC and three HGSCs. AGCT: Adult granulosa cell tumor; AS-SO: adenosarcoma with sarcomatous overgrowth; ATM: ataxia-telangiectasia mutated; CDH1: cadherin 1; EC: endometrioid carcinoma; ERBB2: erb-b2 receptor tyrosine kinase 2; FOXL2: forkhead box L2; MET: c-mesenchymal-epithelial transition factor proto-oncogene, receptor tyrosine kinase; NOTCH1: neurogenic locus notch homolog protein 1; PBRM1: protein polybromo-1; TET2: tet methylcytosine dioxygenase 2.
Baseline clinicopathological characteristics of OCCCs harboring TERTp mutation. Table II summarizes the clinicopathological characteristics of patients with TERTp-mutant OCCC. The age of patients with TERTp-mutant OCCC ranged from 28 to 87 years (mean=51.3 years). The initial FIGO stages were IA (1/11, 9%), IC (3/11, 27%), IIA (1/11, 9%), IIIA1 (2/11, 18%), IIIC (1/11, 9%), and IVB (3/11, 27%). More than half of the patients had an advanced-stage disease. The residual tumor size after primary debulking surgery was ≤1 cm in all but one case. Despite postoperative platinum-based chemotherapy, all patients experienced tumor recurrence. Eight of the 11 patients (72.7%) developed disease progression within six months of the start of postoperative chemotherapy (platinum-resistant recurrence). Six (54.5%) tumors harbored either ARID1A (3/6) or PIK3CA (3/6) mutations and one (9.1%) had pathogenic mutations in both genes.
Baseline clinicopathological characteristics of patients with ovarian telomerase reverse transcriptase promoter-mutant clear cell carcinoma.
Clinicopathological significance of TERTp mutation in OCCC. Table III summarizes the association between the TERTp mutational status and clinicopathological characteristics of patients with OCCC. We found significant correlations among TERTp mutations, postoperative recurrence (p<0.001), and platinum resistance (p<0.001). In particular, all examined patients with OCCC harboring TERTp mutations (11/11; 100.0%) developed recurrent disease, whereas most of the patients with OCCC harboring TERTp-wild type (27/36; 75.0%) did not develop postoperative tumor recurrence. Similarly, the majority of patients (30/36; 83.3%) with TERTp-wild type tumors did not experience tumor progression within six months after the last chemotherapy, whereas eight of 11 patients (72.7%) with TERTp-mutant OCCC were classified as platinum-resistant because recurrent tumors were identified within six months after chemotherapy. There were no significant differences in age (p=0.883), initial FIGO stage (p=0.784), or residual tumor size after primary debulking surgery (p=1.000) according to the TERTp mutational status. We observed no significant association between mutations in TERTp and those in ARID1A (p=1.000) or PIK3CA (p=0.303).
Clinicopathological significance of telomerase reverse transcriptase promoter (TERTp) mutation in patients with ovarian clear cell carcinoma.
Prognostic significance of TERTp mutations in OCCC. Table IV summarizes the results of univariate analyses for DFS and OS in patients with OCCC. The initial FIGO stage (p=0.019), postoperative residual tumor size (p=0.016), and TERTp mutation (p=0.006) were significant predictors of DFS. The hazard ratio for TERTp mutation was estimated at 3.61 (95% confidence interval=1.32-9.86); patients with TERTp-mutant OCCC showed a 3.6-fold higher risk of disease recurrence compared with those with TERTp-wild type tumors. As shown in Figure 2A, the DFS of patients with TERTp-mutant OCCC decreased rapidly over time compared to those with TERTp-wild type tumors. In contrast, TERTp mutations were not significantly associated with worse OS (p=0.769; Figure 2B). Initial FIGO stage was the only significant predictor of OS (p=0.013).
Univariate survival analysis in patients with ovarian clear cell carcinoma.
Differences in the survival of patients with ovarian clear cell carcinoma (OCCC) according to the telomerase reverse transcriptase promoter (TERTp) mutational status. (A) Patients with TERTp-mutant OCCC showed significantly worse disease-free survival (p=0.006) than those with TERTp-wild type tumors. (B) There was no significant difference (p=0.769) in overall survival between patients with TERTp-mutant and -wild type OCCC.
Histological features of TERTp-mutant OCCC. We examined whether there were significant differences in the histological parameters between TERTp-mutant and TERTp-wild-type OCCCs. We assessed the following histological characteristics and compared their frequencies between the two groups: dominant architectural pattern (tubulocystic, papillary, and solid), marked nuclear pleomorphism, brisk mitotic activity (>10 per 10 high-power fields), and tumor cell necrosis. Figure 3 shows representative photomicrographs of the histological features of OCCC. The tubulocystic architecture was characterized by compact, aggregated small tubules and cystically dilated glands with necrotic debris (Figure 3A). Complex branching papillae, with or without hypocellular fibrovascular cores protruding into the cystic spaces, were also observed (papillary architecture; Figure 3B). In some cases, large sheets of tumor cells with scattered myxoid substances and hyaline globules were observed (solid architecture; Figure 3C). Cytologically, most cases exhibited uniform nuclear atypia without brisk mitotic figures (Figure 3D). However, a few cases of TERTp-mutant OCCC displayed aggressive pathological features, including marked nuclear pleomorphism (severe nuclear enlargement with membrane irregularity, prominent macronucleoli, occasional multinucleation, and atypical mitoses; Figure 3E), brisk mitotic figures (Figure 3F), and tumor cell necrosis (Figure 3G). Table V summarizes the associations between the mutational status of TERTp and histological characteristics of OCCC. TERTp-mutant OCCC showed papillary architecture more frequently than those without TERTp mutations (p=0.021). The frequency of aggressive pathological features was not significantly different between the two groups.
Histological features of telomerase reverse transcriptase promoter (TERTp)-mutant ovarian clear cell carcinoma (OCCC). (A-C) The tumor shows various growth patterns. (A) Tubulocystic architecture: closely packed small tubules are admixed with variable-sized cysts possessing necrotic debris. (B) Papillary and micropapillary architecture: complex branching papillae with or without hypocellular fibrovascular cores protrude into the cystic spaces. (C) Solid architecture: within large sheets of tumor cells, myxoid substances (blue arrows) and hyaline globules (black arrows) are scattered. (D-G) Even though OCCC typically shows (D) uniform nuclear atypia without brisk mitotic figures, a few cases of TERTp-mutant OCCC display aggressive pathological features. (E) Marked nuclear pleomorphism: one case of TERTp-mutant OCCC displays severe nuclear enlargement with membrane irregularity, prominent macronucleoli, occasional multinucleation, and atypical mitoses (yellow arrows). (F) Brisk mitotic figures: mitotic figures (green arrows) are readily identifiable. Also note an atypical mitotic figure (yellow arrow). (G) Tumor cell necrosis: large patches of coagulative necrosis are observed. There is an abrupt transition from viable cells to necrotic cells.
Differences in histological features of ovarian clear cell carcinoma according to the telomerase reverse transcriptase promoter (TERTp) mutational status.
Discussion
The promoter mutations of TERT play a fundamental role in the development and progression of various human carcinomas (18-20), and a TERTp mutation is one of the common mechanisms of TERT reactivation. TERTp mutations link the transcription of TERT with oncogenic pathways. TERTp mutations are relatively frequent in several types of malignancies and lead to enhanced expression of telomerase and TERT mRNA (18). The presence of TERTp mutations has been reported to represent the genetic underpinnings of tumor cell immortality, to be associated with poor clinical outcomes, and to define patients with worse survival (21). Griewank et al. (22) observed that TERTp mutations were identified in 42.5% (154/362) of malignant melanoma cases and were independently associated with worse OS. Shaughnessy et al. (23) revealed that TERTp mutations at positions −124 and −146 were associated with the highest levels of TERT mRNA expression and poor prognosis in patients with malignant melanoma. In glioblastoma, TERTp mutations have been reported in approximately 80% of the examined cases (24), but their prognostic impact remains controversial. The frequency and clinical significance of TERTp mutations in breast carcinomas have seldom been investigated. Shimoi et al. (25) reported that TERTp mutations were detected in only three (0.9%) of 319 breast carcinoma cases. In a recent study by Webersinke et al. (26), all examined seven cases of fibromatosis-like metaplastic breast carcinomas typically harbored TERT alterations, including c.1-124C>T mutations (6/7) and copy number gain encompassing the TERT locus (1/7). Kurtis et al. (27) found that 74.4% (64/86) of urothelial carcinoma tissue samples harbored either of the two hotspot TERTp mutations (c.1-124C>T, 54/64; c.1-146C>T, 10/64). These mutations were not associated with tumor location, histological grade, or invasiveness. In thyroid carcinoma, patients with TERTp mutant-tumors showed shorter survival times and more aggressive clinicopathological characteristics than those with TERTp-wild type tumors (28). The average frequency of TERTp mutations in papillary thyroid carcinoma is 10.3% (28).
We found four previous studies that investigated TERTp mutations in OCCC (7, 29-31). As shown in Table VI, the overall frequency of TERTp mutations was 15.7% (83/528). The frequency of c.1-124C>T (14.6% and 14.3%, respectively) was much higher than that of c.1-146C>T (1.3% and 1.8%, respectively) in the first two studies conducted by Wu et al. (29) and Huang et al. (30), whereas similar frequencies of the two mutations were observed in our study (5.6% and 4.7%, respectively). Notably, Nishikimi et al. (7) identified uncommon mutations, including c.1-127C>T, c.1-129G>T, c.1-129G>A, c.1-135G>A, c.1-135G>T, c.1-141G>A, c.1-144C>T, c.1-154C>A, c.1-154C>G, and c.1-154C>T, and their frequencies (14/93; 15.1%) were higher than those of the two common mutations (3.2% for c.1-146C>T and 8.6% for c.1-124C>T). Although Wu et al. (29) observed no significant association among TERTp mutational status, clinicopathological characteristics, and DFS, we found that TERTp mutations were substantially associated with early relapse within six months after chemotherapy and worse DFS. Our findings are consistent with those of Huang et al. (30), who demonstrated a significant relationship between TERTp mutations and early relapse within six months after chemotherapy and worse DFS and OS in patients with early stage OCCC. Nishikimi et al. (7) reported that tumors harboring uncommon TERTp mutations exhibited a more advanced stage and worse progression-free survival than those with common TERTp mutations. The first two studies by Wu et al. (29) and Huang et al. (30) found a strong tendency towards mutual exclusivity between TERTp mutations and PIK3CA mutations or the loss of ARID1A expression, whereas we did not observe any mutual exclusivity between TERTp mutations and mutations in ARID1A or PIK3CA. Further studies with larger numbers of cases are needed to clarify the clinicopathological and prognostic significance of TERTp mutations in patients with OCCC and to examine their association with other pathogenic mutations frequently observed in OCCC.
Previously published reports on telomerase reverse transcriptase promoter (TERTp) mutation in ovarian clear cell carcinoma.
In this study, we observed two uncommon TERTp mutations in three HGSC cases: c.1-245T>C (2/3) and c.1-138/-139CC>TT (1/3). Several studies have documented these TERTp mutations in various human malignancies (23, 29, 32-36). c.1-245 A>G disrupts a pre-existing E26 transformation-specific/ternary complex factor-binding site located 245 bp upstream of the TERT transcription start site and modifies the effect of TERTp mutations (35). It decreases the transcriptional activation of TERT and reverses TERT up-regulation by the promoter mutations. Controversial clinical impacts have been reported from a beneficial effect on OS and limited tumor recurrence in TERTp-mutated bladder urothelial carcinoma (37, 38), renal clear cell carcinoma (39), melanoma (36), and glioblastoma (33, 40), to unchanged or worsened clinical outcome in glioblastoma (41, 42), melanoma (43), hepatocellular carcinoma (36), or differentiated thyroid carcinomas (44, 45). Possible reasons for these conflicting data could be homozygosity versus heterozygosity of the variant or its occurrence on the same allele as other TERTp mutations (35). Further studies are required to assess the relevance of screening for this rare mutation for prognostic and treatment purposes. In case of c.1-138/-139CC>TT, the nucleotide change at −139 bp position is an infrequent polymorphism, represented by rs35550267 (46). An acquired C>T base change at −138 bp position in conjunction with the variant allele at −139 bp position would result in the observed tandem c.1-138/-139CC>TT mutation (46). However, the biological effects of this mutation have not been investigated. c.1-138/-139CC>TT mutation has been suggested to promote greater genomic instability and have a lower effect on TERT upregulation than other types of TERTp mutations (35, 46). Although the prognostic significance of each mutation is debatable, the c.1-138/-139CC>TT mutation has been reported to be associated with poor survival in some previous studies. For example, Nagore et al. (36) observed that the c.1-138/-139CC>TT mutation was associated with the worst DFS and OS in patients with stage I-II melanoma. Further investigation of the differences in clinicopathological characteristics and patient outcomes between different TERTp mutations can help to refine our understanding of the role of these alterations in possible clinical interventions (46).
Conclusion
In conclusion, we analyzed the clinicopathological and molecular characteristics of patients with OCCC harboring TERTp mutations. All examined OCCCs harbored two common TERTp mutations, c.1-124C>T and c.1-146C>T. TERTp mutations were significantly associated with postoperative recurrence and platinum resistance in OCCC. We also demonstrated that TERTp mutations have significant prognostic value for predicting worse disease-free survival in patients with OCCC. Further studies with large cohorts are warranted to confirm the prognostic relevance of this rare mutation in ovarian malignancies.
Acknowledgements
This work was supported by Samsung Medical Center Grant (SMO1230291) and the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (2023R1A2C2006223).
Footnotes
Conflicts of Interest
The Authors declare that they have no conflicts of interest or financial tie related to this study.
Authors’ Contributions
Both Authors made substantial contributions to the conceptualization and design of this study; acquisition, interpretation, and validation of the data; drafting and critical revision of the manuscript; and final approval of the version to be published.
- Received June 22, 2023.
- Revision received August 1, 2023.
- Accepted August 3, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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