Abstract
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 40kb 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.
Highlights
Because of late presentation and chemotherapy resistance ovarian cancer is the deadliest amongst all gynecological malignancies
We demonstrate that the expansion of SOX2-expressing cells within the fallopian tube epithelium is a common feature of high-grade serous ovarian cancers (HGSOCs), a crucial finding that opens new avenues for early disease detection prior to clinical presentation
The number of genes that Genomic Region Enrichment of Annotation Tool (GREAT) assigned to the gene ontology “stem cell differentiation” was 73 and this was the basis of the analysis described above
Summary
Because of late presentation and chemotherapy resistance ovarian cancer is the deadliest amongst all gynecological malignancies. Current methods of detection have been successfully implemented for detection and possible reduction of mortality from ovarian cancer (Menon et al, 2015; Drescher et al, 2013). Such methods are only capable of the detection of established invasive cancers. We established that one mutation is located in a previously unrecognized repressor element of SOX2, an important stem cell gene, and is associated with induction of SOX2 expression. We demonstrate that the expansion of SOX2-expressing cells within the fallopian tube epithelium is a common feature of HGSOCs, a crucial finding that opens new avenues for early disease detection prior to clinical presentation
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