31P - Adult granulosa cell tumours of ovary: Analysis of 227 non-recurrent and recurrent cases

Background

Adult Granulosa Cell Tumours of the ovary (AGCTs) often exhibit slow and indolent growth, resulting in a favourable prognosis and classification as 'low-grade malignant tumours.' This is due to their frequent early-stage detection, allowing for surgical intervention. Despite the generally favourable prognosis, aggressive recurrences occur in 30-50% of cases, typically decades after the initial diagnosis, and can be fatal. The molecular pathogenesis between non-recurrent and recurrent cases is limited. Most AGCTs harbour the recurrent somatic mutation C134W in FOXL2 in 97% of cases. Recently, somatic TERT mutations, recognized as biomarkers for various cancers, have been frequently observed in AGCT patients with recurrence.

Methods

We characterized the DNA of 227 AGCT cases using panel NGS and statistically correlated our findings with clinicopathological data.

Results

The FOXL2 C134W mutation was present in 99% of all cases; a second hit in FOXL2 was detected in 12 cases (5%), both in non-recurrent and recurrent tumours. The second most frequently altered gene was the TERT (promoter), observed in 43% of mutated cases. TERT promoter mutations were significantly more frequent in recurrences compared to primary cases (Pearson chi-square test, p = 0.007). Additionally, mutations in FOXO1 were identified in 7% of cases, with a higher frequency in primary tumours compared to recurrences. Other frequently mutated genes included CHEK2, TP53, and PIK3CA.

Conclusions

This study provides a comprehensive analysis of the clinicopathological and molecular characteristics of AGCTs. Our mutational analysis confirmed the previously reported limited number of recurrent mutations in individual genes in AGCTs and the high prevalence of the FOXL2 p.C134W mutation, consistent with earlier findings identifying this mutation as a hallmark of AGCTs. Interestingly, two primary non-recurrent cases were FOXL2 wild-type, harbouring mutations in KRAS or KMT2D instead. Our findings support the hypothesis that TERT promoter mutations are associated with an increased risk of recurrence and may contribute to poorer overall survival in AGCT patients.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Ministry of Health, Czech Republic (MH CZ AZV NU21-03-00238, DRO-VFN 64165, UNCE 24/MED/018).

Disclosure

All authors have declared no conflicts of interest.