UBC Theses and Dissertations
Adult-type granulosa cell tumour of the ovary : a FOXL2-centric disease Pilsworth, Jessica
Adult-type granulosa cell tumours (AGCT) represent 3-5% of ovarian cancers. AGCT is typically diagnosed at an early stage and is treated by surgery. However, tumour recurrence occurs in one-third of patients, and approximately 50% of relapsed patients succumb to their disease. A somatic missense mutation (c.402C>G; pC134W) in FOXL2 was identified in over 95% of AGCTs. Although this FOXL2 mutation enhanced the ability to accurately diagnose challenging cases, there is still a major clinical challenge in identifying patients that are at risk of relapse and how the FOXL2 C134W mutation contributes to tumourigenesis remains to be elucidated. Objectives: 1) Characterize the genomic and transcriptomic features of AGCT and 2) Develop novel model systems to study the FOXL2 C134W mutation in AGCT Hypotheses: 1) Secondary mutations and/or transcriptional alterations explain the clinical and biological diversity in AGCT and 2) An appropriate cell context and microenvironment is required to understand the role of FOXL2 C134W in AGCT. Methods: Whole genome and targeted sequencing were performed to identify secondary mutations. RNA-Sequencing was performed to describe the transcriptional landscape. Transduction of FOXL2 C134W mutant and hTERT into primary granulosa cells was investigated for the establishment of a de novo transformation model. Development of tumour-derived cell lines and patient-derived xenografts were explored. Results: AGCT is not a disease that cannot be sub-stratified by genomic features. Besides the AKT1 (c.49G>A; pE17K) hotspot mutation identified at a low frequency (2/130, 1.5%) in AGCT, no actionable mutations were identified. TERT C228T promoter mutations were identified in primary AGCTs (51/229, 22%) and recurrent AGCTs (24/58; 41%) suggesting that these mutations play a role in tumour initiation and progression. Transcriptome analysis did not separate AGCTs based on disease status. The transduction of FOXL2 C134W mutant and ectopic expression of TERT into primary granulosa cells was not sufficient for oncogenic transformation. Immortalization of AGCT-derived patient cells and development of patient-derived xenografts were unsuccessful. Conclusions: AGCT represents a specific clinical entity driven by the FOXL2 C402G mutation. Therapeutic strategies focusing on targeting the FOXL2 C134W protein or its downstream consequences are the most promising approach to developing novel treatments for AGCT.
Item Citations and Data
Attribution-NonCommercial-NoDerivatives 4.0 International