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. Author manuscript; available in PMC: 2025 Jul 6.
Published in final edited form as: Int J Gynecol Cancer. 2025 Apr 19;35(8):101862. doi: 10.1136/ijgc-2024-005837

TERT promoter mutations and survival outcomes in adult-type granulosa cell tumors

Allison L Brodsky 1, Alejandra Flores Legarreta 1, Bryan M Fellman 2, Deanna Glassman 1, Jeffrey How 1, Veena Vuttaradhi 1, Anil K Sood 1, Lois Michelle Ramondetta 1, David Gershenson 1, Robert Tyler Hillman 1,3
PMCID: PMC12228831  NIHMSID: NIHMS2078548  PMID: 39395821

Abstract

Objectives

T0 evaluate survival outcomes among patients with adult-type granulosa cell tumors who have telomerase reverse transcriptase (TERT) promoter mutations.

Methods

This is a retrospective cohort study using the MD Anderson Rare Gynecologic Malignancy Registry. Patients with adult granulosa cell tumors who underwent molecular testing for TERT promoter and FOXL2 c.C402G mutations were included. We used descriptive statistics to compare demographic and clinical variables and estimated progression-free and overall survival with Kaplan-Meier curves. Cox proportional hazards regression and log-rank tests were employed for comparisons, with multivariable analyses adjusting for various factors.

Results

Among 70 patients, 28 (40%) had TERT+ tumors. The median age at diagnosis was 40 years (range 12–71) for TERT− patients and 46 years (range 25–76) for TERT+ patients. At diagnosis, 22 (63%) of 35 TERT− patients were stage I, 10 (29%) stage II, and 3 (9%) stage III, while in the TERT+ group, 17/23 (74%) were stage I, 3 (13%) stage II, and 3 (13%) stage II. Univariable analysis showed no difference in time from diagnosis to first recurrence (p=0.19) and from first recurrence to second recurrence (p=0.24) based on tumor TERT status. The median time from first to second recurrence in the TERT− group was 27.3 months (95% CI 14.1 to 40.0) and in the TERT+ group was 14.8 months (95% CI 8.1 to 21.0). There was no observed difference in overall survival between the groups (HR=0.53; 95% CI 0.19 to 1.45; p=0.21). Multivariable analysis adjusting for age at diagnosis, TERT promoter mutation status, systemic chemotherapy, and stage demonstrated a significant difference in progression-free survival based on TERT mutation status (HR=2.89; 95% CI 1.32 to 6.36).

Conclusions

After adjustment for covariates, patients with adult granulosa cell tumors and TERT+ tumors had shorter progression-free survival after first recurrence. TERT promoter mutations may identify a subset of patients with recurrent adult granulosa cell tumors and less favorable outcomes.

INTRODUCTION

Granulosa cell tumors are uncommon tumors that account for 2–5% of ovarian cancers.1 The majority are adult-type granulosa cell tumors, comprising 95% of granulosa cell tumors. Adult granulosa cell tumors tend to have improved outcomes compared with the more common epithelial ovarian tumors. Most adult granulosa cell tumors are cured with surgery alone at the time of diagnosis, but about 30% will recur.2 Adult granulosa cell tumors are an indolent tumor with recurrences reported between 1 and 36 years after initial treatment.2 3 The preferred treatment for recurrence is cytoreduction4 with or without systemic chemotherapy, endocrine therapy, and/or radiation.5–11 Overall, response rates to systemic therapy in recurrent adult granulosa cell tumors have been disappointing. Examples include a phase II trial of anastrozole in adult granulosa cell tumors with a median progression-free survival of 8.6 months9 and a basket trial of onapristone, a progesterone antagonist, with a median progression-free survival of 2.8 months.12 Given the rarity of adult granulosa cell tumors, there are few large-scale randomized clinical trials looking at the ideal treatment for this disease, which is still not established.13

A hallmark of adult granulosa cell tumors is the somatic missense point mutation c.402C>G (p.C134W) in FOXL2.14 A study of 423 adult granulosa cell tumors found that the most common pathogenic variants in these tumors (aside from FOXL2, which was 100% present) are TERT (54%), KMT2D/MLL2 (17%), and CDKN2A (12%).15 Telomerase reverse transcriptase (TERT) is a subunit protein of telomerase which maintains the ends of telomeres by adding repetitive sequences.16 Telomerase is normally silenced in somatic cells, but many tumors gain the function of telomerase to attain capacity for continued proliferation. TERT promoter mutations have been associated with poor prognosis in a variety of different cancers.17–22 One study performed immunohistochemistry evaluation of 88 granulosa cell tumors and found that CD56 and SMAD3 immunohistochemistry expression in primary tumors are independent predictors of recurrence.23 However, this study did not evaluate for TERT promoter mutations.

Clinical factors associated with adult granulosa cell tumor recurrence have not been well established, with many studies showing differing results. Reliance on these results is limited given the small number of patients and often retrospective nature of these studies. Suggested prognostic factors that may increase risk of recurrence in adult granulosa cell tumors include stage at diagnosis, incomplete cytoreduction, and age, but all are controversial with conflicting results from different studies.2 23–26 The use of tumor molecular profiling allows for stratification of outcomes in cancer from a tumor biology standpoint. Our goal was to evaluate the molecular profile of adult granulosa cell tumors to determine if specific mutations are associated with clinical outcomes. Therefore, given that the TERT promoter mutation was the most common mutation in adult granulosa cell tumors, aside from the ubiquitous FOXL2, we aimed to assess the prognosis of patients with TERT mutations in adult granulosa cell tumors.

METHODS

Case Selection

This was a retrospective cohort study involving patients with adult granulosa cell tumors with formalin-fixed, paraffin-embedded tumor molecular testing. This study was conducted according to the guidelines of the Declaration of Helsinki. All patients were enrolled in an institutional review board-approved Rare Gynecologic Malignancy Registry (protocol #PA17–0586). Our registry collects data from two institutions, MD Anderson Cancer Center and Lyndon B Johnson Hospital, both in Houston, Texas, USA. Data collection started in January 1970. All patients provided written informed consent for the tumor registry or had a waiver of informed consent if they had not been seen at MD Anderson or Lyndon B Johnson Hospital for at least 3 years or were deceased. Rare tumors in this registry include malignant germ cell, sex cord–stromal, rare epithelial (carcinosarcoma, clear cell, mucinous), and neuroendocrine tumors.

This registry collects a wide variety of data, including demographics, past medical and surgical history, diagnosis, treatment, pathology records, special tumor testing, recurrence patterns, and outcomes. The use of registry data for these specific analyses was separately approved by the IRB (protocol #2020–1156). The inclusion criteria for this study included patients who had histology-proven diagnosis of adult granulosa cell tumors (juvenile granulosa cell and mixed tumors were excluded) and the adult granulosa cell tumor had formalin-fixed, paraffin-embedded tumor molecular testing using a panel capable of detecting both a TERT promoter mutation and FOXL2 c.C402G mutation. All patients were required to have follow-up data for at least a year after tumor molecular testing to be included in this study.

Data Collection

Study data were collected and managed using REDCap electronic data capture tools hosted at MD Anderson.27 28 REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources. The data collection cut-off date for the present study was February 13, 2024. The following clinical and demographic data were extracted from the registry: age at diagnosis and recurrence/progression events, stage, race/ethnicity, treatment center, tumor histology, cancer treatment history (surgical and medical management in the front-line and recurrent setting), recurrence patterns/history, and vital status.

Statistical Analyses

Descriptive statistics were used to summarize the demographic and clinical characteristics of the study population. We estimated progressions beyond initial progression. For example, progression-free survival 2 was defined from the date of first progression to the earliest date of the second progression or death. Subjects who were alive and known not to have second progression survival time were censored at the last clinic visit seen and assessed for progression. Progression-free survival X was estimated with the methods of Kaplan and Meier, significance determined with the log-rank test, and modeled via Cox proportional hazards regression. Overall survival was defined from date of diagnosis to earliest date of death or last contact. All statistical analyses were performed using Stata/MP v17.0 (College Station, Texas, USA).

RESULTS

The rare tumor registry had 380 patients with adult granulosa cell tumors at the time of data retrieval. Two hundred and ninety-five patients were excluded from our study given no formalin-fixed, paraffin-embedded tumor molecular testing. A further 15 patients were excluded due to no FOXL2 testing (n=11), negative FOXL2 testing (n=1), no TERT promoter mutation testing (n=1), and mixed histology tumors (n=2). Therefore, a total of 70 patients were included in the analysis set. Of these cases, 40% (28/70) had TERT promoter mutations (TERT+). Table 1 includes demographic and clinical characteristics of the study population. The median age at time of diagnosis for TERT unmutated (TERT−) patients was 40 years (range 12–71) and for TERT+ patients was 46 years (range 25–76). Of patients with TERT− tumor, 63% were stage I, 29% were stage II and 9% were stage III at time of diagnosis. In the TERT+ group, 74% were stage I, 13% were stage II, and 13% were stage III at time of diagnosis There were no significant differences in age at time of diagnosis (p=0.21), initial stage (p=0.46), first-line treatment (p=0.37) or demographics between TERT+ and TERT−) adult granulosa cell tumors. The median follow-up (from first progression) for all patients was 83.6 months (range 2.9–305.5).

Table 1.

Demographics and clinical characteristics of patient population

Characteristics TERT negative TERT positive P value
N % N %
Age at the time of diagnosis (years) 0.21
 Mean (SD) 42.48 (12.98) 46.57 (13.86)
 Median (min-max) 40.00 (12.00–71.00) 46.00 (25.00–76.00)
Stage 0.46
 I 22 62.9 17 73.9
 II 10 28.6 3 13.0
 III 3 8.6 3 13.0
Ethnicity 0.13
 Hispanic or Latino 7 17.5 1 3.6
 Not Hispanic or Latino 33 82.5 27 96.4
Race 0.76
 Asian 4 9.5 2 7.1
 Black/African American 6 14.29 3 10.7
 Other 4 9.5 1 3.6
 White 28 66.7 22 78.6
First-line treatment 0.37
 Surgery 24 57.1 19 67.9
 Surgery+systemic therapy 18 42.9 9 32.1
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SD, standard deviation; TERT, telomerase reverse transcriptase.

There are two somatic point mutations of the TERT promoter noted in adult granulosa cell tumors, C228T and C250T.16 Of the patients with a TERT+ tumor, 68% (19/28) had the C288T mutation, 14% (4/28) had the C250T mutation, and in 18% (5/28) of patients the type of mutation was not identified. The median time from diagnosis to first progression, progression-free survival 1, in the TERT− group was 49.3 months (95% CI 33.6 to 57.2) and in the TERT+ group was 65.9 months (95% CI 35.1 to 90.8). There was no observed difference in progression-free survival 1 (p=0.19, Figure 1A). Among those patients with at least one recurrence, there was no observed difference in time to progression between first and second recurrence (p=0.24; progression-free survival 2) between patients with TERT+ and TERT− adult granulosa cell tumors (Figure 1). The median progression-free survival 2 for all subjects was 17.7 months (95% CI 13.5 to 31.5). The median progression-free survival 2 in the TERT− group was 27.3 months (95% CI 14.1 to 40.0) and in the TERT+ group was 14.8 months (95% CI 8.1 to 21.0). When including only those patients who underwent cytoreduction at second recurrence, there was no observable difference in progression-free survival 2 (p=0.85) for TERT + (n=18) compared with TERT− (n=37) adult granulosa cell tumors. Median overall survival from time of diagnosis was 273 months for TERT− and 379 months for TERT+ tumors. There was no observed difference in overall survival based on TERT status (HR=0.53; 95% CI 0.19 to 1.45; p=0.21), as demonstrated in Figure 2.

Figure 1.

Figure 1

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(A) Kaplan-Meier curve from diagnosis to first progression for TERT+ versus TERT− adult granulosa cell tumors. (B) Kaplan-Meier curve from first to second progression for TERT+ versus TERT− adult granulosa cell tumors. TERT, telomerase reverse transcriptase.

Figure 2.

Figure 2

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Kaplan-Meier curve for overall survival from time of diagnosis comparing TERT+ versus TERT− adult granulosa cell tumors. TERT, telomerase reverse transcriptase.

Multivariable analysis adjusting for age at diagnosis, TERT promoter mutation status, systemic chemotherapy, and stage at time of diagnosis was performed, shown in Table 2. A significant difference in progression-free survival 2 was not demonstrated when adjusting for treatment with systemic chemotherapy (HR=1.09; 95% CI 0.54 to 2.2), or stage I versus stage II–IV at time of diagnosis (HR=0.87; 95% CI 0.40 to 1.93). Multivariate analysis did demonstrate a significant difference in progression-free survival 2 based on TERT mutation status (HR=2.89; 95% CI 1.32 to 6.36). KMT2D is the second most common mutation in adult granulosa cell tumors after TERT, excluding the ubiquitous FOXL2 mutation. Of the 28 TERT+ tumors, 14 had testing for a KMT2D mutation and 3 were positive. Of the 28 TERT+ tumors, 25 had testing for a TP53 mutation and only one was positive.

Table 2.

Multivariable analysis for progression-free survival after first recurrence

Characteristic N HR (95% CI) P value
PFS2* Age ≥60 53 2.68 (1.03 to 7.01) 0.044
Stage II-IV 15 0.87 (0.40 to 1.93) 0.74
TERT mutation 21 2.89 (1.32 to 6.36) 0.008
Chemotherapy at first progression 30 1.09 (0.54 to 2.20) 0.80
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*

Progression-free survival 2, time from first recurrence to second recurrence.

TERT, telomerase reverse transcriptase.

Of the 28 TERT+ tumors, formalin-fixed, paraffin-embedded molecular testing was done at time of diagnosis on 4 (14%) of patients. The remaining 24 patients (86%) had formalin-fixed, paraffin-embedded molecular testing done at the time of recurrence. Timing of molecular testing ranged from first recurrence to ninth recurrence. Four patients had serial formalin-fixed, paraffin-embedded somatic testing; all testing was done on recurrent tumors. Three patients retained TERT mutations at all time points of formalin-fixed, paraffin-embedded testing of their tumors. One patient had a TERT+ tumor at time of second recurrence; testing was also positive for FOXL2, SLIT2, and CDKN2A/B. Testing was done on a sigmoid nodule. At the time of subsequent recurrence 1 year later, tumor testing was done on a new sigmoid nodule and was found to be negative for a TERT mutation. The molecular panel did have the capability of detecting a TERT promoter mutation; the patient was found to have a tumor positive for FOXL2 and SETD2.

DISCUSSION

Summary of Main Results

Seventy patients with adult granulosa cell tumors and formalin-fixed, paraffin-embedded tumor molecular testing were included in this study, 40% (28/70) of whom had TERT+tumors. Between TERT+ and TERT− tumors, there was no difference in time from diagnosis to first progression and time from first to second progression. While there was no significant difference in progression-free survival 2 (p=0.24) between TERT+ and TERT− tumors, there was a nearly twofold decrease in progression-free survival 2 in TERT+ tumors, which is clinically relevant. Furthermore, multivariable analysis demonstrated that TERT+ adult granulosa cell tumors had worse outcomes for progression-free survival 2 compared with TERT− adult granulosa cell tumors. The twofold change in progression-free survival 2 and the findings of worse progression-free survival 2 outcomes with multivariable analysis may be explained by TERT mutations developing after the first recurrence and contributing to worsened prognosis. There was no observed difference in overall survival between TERT− and TERT+ adult granulosa cell tumors. There was no difference in progression-free survival 2 between patients with TERT+ and TERT− who did and did not undergo cytoreductive surgery.

Results in the Context of Published Literature

Literature has shown that TERT promoter mutations tend to be present to a greater extent in recurrent adult granulosa cell tumors compared with primary tumors.29 30 A study of 38 adult granulosa cell tumors found a higher frequency of TERT promoter mutations in recurrent adult granulosa cell tumors (64%) compared with primary non-recurrent and primary recurrent adult granulosa cell tumors (26%).30 This could explain the lack of difference in time to first progression between TERT+ and TERT− adult granulosa cell tumors; the majority of tumors did not yet possess the TERT promoter mutation. This is speculative, however, as the majority (24/28, 86%) of TERT+ patients had tumor molecular testing done at the time of recurrence, and therefore data are missing on whether TERT mutation was present at the time of diagnosis or was acquired with subsequent recurrences.

TERT promoter mutations have been associated with poor prognosis in a variety of different cancers.17–22 TERT mutations are not common among gynecologic malignancies. Wu et al. performed sequencing analysis on 525 gynecologic tumor samples.31 They found no TERT mutations in endometrioid or high-grade serous ovarian cancer and only 3.3% (1/30) in low-grade serous ovarian cancers. No TERT mutations were found in leiomyosarcomas or endometrioid and serous endometrial cancers. No TERT mutations were found in adenocarcinoma of the cervix and only 3.8% (2/52) squamous cell cervical cancers had TERT mutations. Further study of clear cell ovarian tumors with TERT mutations found that TERT was associated with a shorter disease-free survival and overall survival.32

In contrast to other gynecologic malignancies, TERT mutations are more frequent in adult granulosa cell tumors. Our study demonstrated a rate of 40% (28/70). This pattern of higher TERT mutation burden in recurrent adult granulosa cell tumors has been seen in multiple studies.16 29 30 A prior study of 186 adult granulosa cell tumors found that the TERT mutation was associated with a difference in overall survival but not disease-specific survival or disease-free survival.16 However, the study looked only at first recurrence and not subsequent recurrences. Our study shows that TERT mutated adult granulosa cell tumors, through multivariate analysis, are associated with shorter progression-free survival 2 compared with TERT wild-type tumors. Our study is also the first to examine whether cytoreduction specifically improves or worsens outcomes for TERT mutated tumors, and no significant change in prognosis was noted.

Strengths and Weaknesses

A strength of this study is our Rare Gynecologic Malignancy Registry with over 400 patients with adult granulosa cell tumors. The database has long term follow-up with median follow-up being 7 years for patients still alive. However, the small sample size for formalin-fixed, paraffin-embedded tested tumors did limit the ability to detect significant differences in this study. Furthermore, all formalin-fixed, paraffin-embedded molecular testing was done on recurrent adult granulosa cell tumors, rather than primary tumors. Minimal serial sequencing limited the ability to detect TERT mutations over time in the same patient.

As this study is retrospective, inherent limitations do exist. The study is limited by the data available in the medical record, and misclassification bias is possible. Additionally, selection bias might have influenced patient selection and potential confounding variables might not have been assessed. We did observe some significant differences, but this analysis did not have proper power analysis and sample size justification for hypothesized values, so values should be interpreted cautiously.

Implications for Practice and Future Research

TERT mutated adult granulosa cell tumors in our study are associated with a worse prognosis regarding progression-free survival 2 and can be discussed with patients when considering future treatment options. Future research includes further study of TERT mutated adult granulosa cell tumors in the context of treatment type at each recurrence. Larger cohorts can confirm if certain treatments would allow these patients with a poor prognosis a better response.

One patient with serial molecular testing was found to develop a TERT mutation in subsequent recurrences. Future research could aim to perform either retrospective or prospective serial molecular testing of adult granulosa cell tumors. Analysis of survival outcomes in conjunction with development of TERT mutations could provide new and relevant prognostic factors.

CONCLUSIONS

After adjustments for covariates, TERT mutated adult-type granulosa cell tumors were associated with worse prognosis after first recurrence compared with TERT wild-type adult-type granulosa cell tumors. There was no observed difference in overall survival between TERT mutated and TERT wild-type, adult granulosa cell tumors.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Telomerase reverse transcriptase (TERT) mutations are associated with a poor prognosis in many cancers but are overall rare in gynecologic cancers.

WHAT THIS STUDY ADDS

  • This retrospective cohort study demonstrates that TERT mutated adult granulosa cell tumors are associated with shorter progression-free survival intervals.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • This data may suggest use of more aggressive treatment, including both cytoreductive and systemic treatment, in patients with adult granulosa cell tumors and a somatic TERT mutation.

Acknowledgements

We thank all the patients who participated in this study.

Funding

This research was in part supported by the National Institutes of Health through MD Anderson’s Cancer Center Support Grant CA016672. This research was supported in part by Cancer Prevention & Research Institute of Texas grants RR2000045 (R.T.H.). This work was also supported by the NIH/NCI under award numbers T32 CA101642 (D.G. and A.L.B.). Additional funding sources include the Jennifer “Jenny” Song Fund for Granulosa Cell Tumor Research, Alisha B. Smith GCT Hope Fund, The University of Texas MD Anderson Cancer Center Ovarian Cancer SPORE (NIH grant CA281701), the American Cancer Society (AKS), the Ovarian Cancer Research Alliance (AKS), and the Frank McGraw Memorial Chair in Cancer Research (AKS).

Footnotes

Publisher's Disclaimer: This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclaimer These aforementioned funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Competing interests AKS reports consulting fees from Merck, Iylong, Astra Zeneca, Onxeo, ImmunoGen, GSK and participation on a data safety monitoring board for Advenchen.

Ethics approval This study involves human participants and all patients were enrolled in an institutional review board (IRB)-approved Rare Gynecologic Malignancy Registry (protocol #PA17-0586). The use of registry data for these specific analyses was separately approved by the IRB (protocol #2020-1156). Participants gave informed consent to participate in the study before taking part.

Data availability statement

Data are available upon reasonable request. If data were to be made available, it would need to be done under material transfer agreement through MD Anderson Cancer Center.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data are available upon reasonable request. If data were to be made available, it would need to be done under material transfer agreement through MD Anderson Cancer Center.

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