Environmental risk factors The ‘incessant ovulation’ theory is suggested by the strong correlation between the number of ovulatory cycles of an individual and their risk of ovarian cancer. This trend is reflected in the protective effects of pregnancy, parity and breastfeeding against ovarian cancer, and similar findings in epidemiological studies that have indicated a reduction of risk associated with use of oral contraceptive pills. Ovulation is accepted as the cause of ovarian cortical inclusion cysts, the precursor lesions of serous carcinomas, and lower numbers of these cortical inclusion cysts are thought to be the mechanism by which reducing lifetime ovulations can lower the risk of developing HGSC. Conversely, a temporal association with menopausal hormone therapy and incidence of HGSC was found, and polycystic ovarian syndrome (PCOS) was shown to contribute to a doubling of the risk of ovarian cancer. Endometriosis can increase risk for other ovarian cancer subtypes, but is not associated with HGSC. Genetic risk factors More than 20% of ovarian cancer tumours have hereditary origin. The majority of these feature mutations in the tumour suppressor BRCA genes, which tend to give rise to HGSC. A mutation in BRCA1 or BRCA2 can confer a lifetime ovarian cancer risk of 40-50% and 10-20% respectively, with BRCA2 mutations strongly associated with better clinical outcomes. A specific tumour protein 53 (TP53) expression pattern in the Fallopian tube epithelium – the ‘p53 signature’ - is thought to be a precursor marker of HGSC. TP53-/- mice (in which the TP53 gene has been deleted) do not develop ovarian carcinomas. However, TP53 mutations were found in 96% of HGSC cases. A local abnormal TP53 expression may thus be indicative of HGSC. In women, pelvic HGSC show either a complete absence of P53 expression, or overexpression, suggesting that any aberration of P53 leads to tumour development. Additionally, overexpression of TP53 is associated with better clinical outcome whereas an absence of the p53 protein is linked to an increased risk of HGSC tumour recurrence. A recent mouse model suggest that a p53 mutation may induce HGSC arising from the ovary rather than the Fallopian tube.
High-grade serous carcinoma
Endometrial stromal sarcoma
Adenomyomatosis
Uterine clear-cell carcinoma
Endometrial stromal tumour
Tubular carcinoma
Uterine serous carcinoma
Papillary serous cystadenocarcinoma