Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

• Dense sequencing of an ovarian cancer identifies founder non-coding mutations.
• Fallopian tube SOX2 overexpression is a common premalignant feature in ovarian cancer.
• The expression of SOX2 and MYC in the fallopian tube appears mutually exclusive.A major obstacle for effective early detection of ovarian cancer is that CA125 and ultrasound can only detect established ovarian cancer. Currently proposed pre-cancer lesions are not amenable to clinical detection because they affect only a small number of cells. In this work we demonstrated that pre-cancer SOX2 overexpression in the FTE is nearly ubiquitous in HGSOCs and is also a common feature in women with BRCA1 and BRCA2 mutations prior to ovarian cancer initiation. Thus, our data has important implications for screening, although it will need additional clinical evaluation to test the feasibility of quantitative detection of SOX2 expression or the expression of its downstream targets for this purpose.

Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40 kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p < 2−16), which was not found in patients without cancer (n = 108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n = 100), and common in BRCA1-BRCA2 mutation carriers (n = 71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.