Juvenile granulosa cell tumour (jGCT) is a rare ovarian tumour mainly affecting young woman and children. Patients with advanced or recurrent jGCT often face a poor prognosis. The molecular pathogenesis remains unclear. While a small number of mutations have been reported, their significance has yet to be fully elucidated. In this study, we sought to characterise the genomic landscape of jGCT using whole genome sequencing (WGS).
Six jGCT samples, including five formalin-fixed paraffin-embedded (FFPE) and one fresh-frozen sample, were sequenced along with matched germline DNA on the MGI platform at BGI. Sequencing data were then processed using the nf-core/sarek pipeline, and small variants were detected using two variant callers, Mutect2 and Strelka2. Variants identified by the consensus of both callers were subjected to further analysis.
The number of variants detected in each patient ranged from 10,000 to 30,000. Notably, the previously reported mutations in AKT1 and DICER were not found in this cohort. However, the previously reported GNAS mutations at Arg201, were found in two cases, and an IDH1 mutation (Arg132) was detected in one patient. Additionally, three gene variants (PLEC, TGFBR1/ALK5, TP53) were identified, each across two different patients. Of particular interest, a previously unreported heterozygous variant in TGFBR1 (p.Gly325Val), was found in two patients. This variant, in a highly conserved residue, is predicted to activate the SMAD2/3 signalling pathway. Surprisingly, both the GNAS and TGFBR1 gene variants were present in the same two patients. Furthermore, unique variants in the PLEC gene, which encodes plectin, a ubiquitously expressed versatile cytolinker and scaffolding protein, have not been previously reported in cancer databases.
In contrast to adult granulosa cell tumours, which are defined by a unique FOXL2 mutation, jGCT appear to exhibit significant genetic heterogeneity. This suggests that a personalised molecular approach may be necessary to identify potential therapeutic strategies for patients with jGCT.