Despite significant progress in the past two decades in differentiating the major histological types of epithelial ovarian carcinoma (EOC), much remains to be determined and understood regarding the pre-invasive counterparts to these lesions. We have undertaken molecular characterization of benign and borderline ovarian tumours of mucinous (N=42) and serous (N=92) histology using high-resolution genome-wide copy number analysis, mutation hotspot screening, immunhistochemistry and exome sequencing.
In the mucinous cohort we identified a highly consistent activation of RAS/RAF family members and increasing co-occurrence of loss of p16 (CDKN2A) from mucinous cystadenoma to mucinous borderline tumour to invasive carcinoma. These mutation events occurred early, being identifiable in 90% of mucinous cystadenomas. In stark contrast, only 2% serous cystadenomas and cystadenofibromas had detectable copy number aberrations. Additionally, in contrast to the consistent copy number aberrations targeting p16 in the mucinous tumours, serous borderline tumours appear relatively heterogeneous at the copy number level. Intriguingly, specific clinical features and copy number events were found to be significantly associated with either KRAS or BRAF mutation status, indicating distinct biological consequences arising from these oncogenic events.
Despite the known overlaps in the mutation spectrum of mucinous and serous ovarian tumours, these analyses identified histology-specific patterns of copy number aberration and novel mutation events. These findings highlight some of the fundamental molecular contradistinctions of these histologies that are likely to be influencing relative response to standard EOC treatment. Understanding precursor biology contextualises tumour biology, informs tumour progression models, and assists identification of biomarkers and biologically relevant molecular targets.