title: Dissecting the molecular landscape of synchronous endometrial and ovarian carcinoma and the aetiology of endometriosis-associated ovarian carcinoma
Creators: name: Southworth, Emily Christine
Publisher: name: The University of Edinburgh
Year: 2025
Subjects: subject: Synchronous carcinoma
subject: Endometriosis
subject: Genomic relatedness
subject: Whole exome sequencing
subject: Mutational burden

description: Epithelial ovarian cancer, or ovarian carcinoma, is a group of diseases which can be characterised by histopathological subtype (‘histotype’). Ovarian endometrioid and ovarian clear cell carcinoma each account for 10% of ovarian carcinoma cases; these histotypes are regarded as ‘endometriosis associated ovarian carcinoma’. Endometriosis is a benign condition that describes the presentation of endometrial tissue in extra-uterine sites, often in the ovaries. Ovarian endometriosis may be the precursor lesion to endometriosis-associated ovarian carcinoma. Synchronous endometrial and ovarian carcinoma accounts for 5% of endometrial cancer and 10% of ovarian cancer cases; both tumours are typically organ-confined, low grade, and endometrioid in histotype. Synchronous endometrial and ovarian carcinoma remains distinct from metastatic disease; accordingly, a subset of patients receive conservative management as per clinicopathological criteria. But, almost all studied tumour pairs share identical genomic aberrations. Consequently, it is now widely accepted that synchronous endometrial and ovarian carcinomas likely arise from a common origin, raising the question of how patient outcome is so good, if they are indeed metastatic tumours. This body of work aims to elucidate the molecular and mutational characteristics of synchronous endometrial and ovarian carcinoma. This data was also used to determine the extent of genomic relatedness between tumour pairs. Firstly, using the Edinburgh Ovarian Cancer Database, suspected synchronous cases were selected for formalin-fixed paraffin-embedded (FFPE) tissue review. Immunohistochemistry (IHC) was performed to stain tumours from 34 synchronous cases for known diagnostic markers, aiding histotype identification. Tumour material from each tumour site was then taken forward for further IHC to understand the prevalence of relevant protein expression patterns. Expression profiles of such proteins in synchronous disease are typically those of the ovarian and endometrial carcinomas of the same histotypes. Whole exome sequencing was possible in 27 of 34 synchronous tumour pairs. The most frequently mutated genes in synchronous tumours were similar across tumour sites. Several genes were significantly more frequently mutated in synchronous disease than endometriosis-associated ovarian carcinoma and endometrioid endometrial carcinoma. Tumour mutational burden (TMB) remained low, with an increase in tumours expected to be ‘hypermutated’ (mismatch repair deficient) and ‘ultramutated’ (POLE mutant). Single nucleotide variants (SNVs) were the most common mutation type present, with the COSMIC SBS ageing signatures SBS1 and SBS5 most prevalent. The above data was then used to assess relatedness between the 27 paired synchronous tumours. Notably, all tumour pairs shared identical mutations, with the overlap of mutations occurring as a range. Other WES-derived parameters, such as statistically significant differences in mutational signature contribution, relative difference in TMB and relative difference in mutant allele tumour heterogeneity (MATH), were also useful in assessing the extent of genomic relatedness between tumour pairs. Lastly, FFPE tissue from 11 endometriosis-associated ovarian carcinoma cases with identifiable ovarian endometriosis adjacent to carcinoma underwent IHC. This revealed distinct features that may be of relevance to the mechanism by which ovarian endometriosis may progress to malignancy. In vitro work was then carried out to understand the role of β-catenin overexpression, a consequence of CTNNB1 hotspot mutation, a frequent event in the synchronous cohort, on the morphology, and migratory and invasive potential of endometriosis. Taken together, this body of work presents further characterisation of an uncommon gynaecological cancer type of biological and genomic interest. Such data may be beneficial to clinicians in light of recent, stringent changes to conservative management criterion for synchronous primary endometrial and ovarian carcinoma. Furthermore, this work may identify biological events involved in the development of endometriosis-associated ovarian carcinoma in patients with endometriosis.