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

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 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.

Serous tubal intraepithelial carcinomas associated with high‐grade serous ovarian carcinomas: a systematic review

“…This highlights the need for additional complementary strategies for effective prevention of HGSOCs. Recent work has identified promising biomarkers that may become useful in this regard …”

“…Recent evidence showed that precursor lesions arise from the secretory cell type of the fallopian tube epithelium (FTE) making it a plausible site of origin for HGSOC . These lesions are described as serous tubal intraepithelial carcinomas (STICs), and show stratification, loss of polarity, increased mitotic activity, marked nuclear pleomorphism, hyperchromasia, prominent nucleoli and overexpression of the tumour suppressor protein TP53 (also commonly referred to as p53) …”

Sex-determining region Y box-containing genes: regulators and biomarkers in gynecological cancers

“…Thus, there is an urgent need to find novel diagnostic biomarkers for detecting OC at a premalignant stage 33 . SOX genes are identified as such biomarkers that can contribute to early screening and the prediction of clinical features in patients with OC, and regulation of SOX gene expression could influence cell proliferation and treatment efficacy at the cellular level 9,10,16,18,31,34 . …”

“…On one hand, high SOX expression level in fallopian tube epithelium was exploited as a biomarker for OC screening, especially in BRCA1 or BRCA2 mutation carriers or in women with serous OC in high grade 16 . High expression level of SOX2 in patient samples was also shown to be related to high grade, advanced FIGO stage, and decreased DFS 36,37 .…”

“…Furthermore, regulating expression level of SOX genes in certain cancer cell lines could influence cell proliferation and apoptosis in vitro but without known mechanisms 12,13 . Additionally, analysis of abnormal SOX genes expression in patient samples contributed to the detection of early GC lesions 14-16 . Expression level of SOX genes was also considered as biomarkers associated with clinical features in patients with GCs, including International Federation of Gynecology and Obstetrics (FIGO) stage, histopathologic grade, and disease-free survival (DFS), as well as treatment response 10,15,17-19 .…”