Ovarian Adult Granulosa Cell Tumors: A Scoping Review of DNA Alterations and Their Known Significance

Background/aim: Adult granulosa cell tumor (aGCT) is a rare and challenging ovarian tumor due to its unpredictable recurrence and its associated increased risk of breast and endometrial cancer. Identifying and describing molecular alterations in tumors has become common with the advent of high-throughput sequencing. However, DNA sequencing in rare tumors, such as aGCT, often lacks statistical power due to the limited number of cases in each study, thereby clinical implications of DNA alterations are difficult to interpretate. This scoping review aims to systematically describe somatic and germline DNA alterations identified in women with aGCT.

Materials and methods: Search terms (granulosa cell tumour AND molecular alterations) were searched in May 2024 in the following databases: MEDLINE (Ovid), Embase (Ovid), Web of Science Core Collection and Google Scholar. Screening, full-text review and data extraction were performed by two independent reviewers.

Results: Twenty-four publications were identified. Eighteen reported on somatic DNA alterations of patholgenic mutations identified in total 1,226 tissues being sequenced. FOXL2 (c.402C>G; p.C134W) was present in 97% of aGCTs. Other pathogenic mutations in the tissues investigated were TERT promoter mutation (41%), truncating KMT2D mutations (14%) and TP53 pathogenic variant (4%). TERT promoter mutation was reported more frequently in recurrent tumors (p<0.01), whereas comparing truncating KMT2D and TP53 mutations reported in primary and recurrent tumors revealed no difference (p=0.15 and p=0.26 respectively). Tumor mutational burden (TMB) was reported in five studies and all showed a low TMB. None of the somatic mutations were candidate targets for biological treatment. Six publications reported germline variants and no shared germline pathogenic variants were described in the published literature.

Conclusion: The FOXL2 missense mutation was the only common somatic DNA alteration in aGCT. TERT promoter mutations were reported more frequently in recurrent aGCT but their clinical relevance remains uncertain. In contrast to previous reports, truncating KMT2D mutations were not found to be associated with recurrent aGCT. Evidence on common germline variants in aGCT is sparse. The role of somatic and germline DNA alterations in the development of other malignancies in women with aGCT remains uncertain. Further research involving matched primary and recurrent tumors, as well as other primary malignancies, is essential to better understand the mutations that drive tumor development.