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

Karin Hellner, Fabrizio Miranda, Donatien Fotso Chedom, Sandra Herrero-gonzalez, Daniel M. Hayden, Rick Tearle, Mara Artibani, Mohammad Karaminejadranjbar, Ruth Williams, Kezia Gaitskell, Samar Elorbany, Ruoyan Xu, Alex Laios, Petronela Buiga, Karim Ahmed, Sunanda Dhar, Rebecca Yu Zhang, Leticia Campo, Kevin A. Myers, María LozanoMaría Ruiz-miró, Sónia Gatius, Alba Mota, Gema Moreno-bueno, Xavier Matias-guiu, Javier Benítez, Lorna Witty, Gil Mcvean, Simon Leedham, Ian Tomlinson, Radoje Drmanac, Jean-baptiste Cazier, Robert Klein, Kevin Dunne, Robert C. Bast, Stephen H. Kennedy, Bassim Hassan, Stefano Lise, María José Garcia, Brock A. Peters, Christopher Yau, Tatjana Sauka-spengler, Ahmed Ashour Ahmed

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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.
Original languageEnglish
Pages (from-to)137-149
JournalEBioMedicine
Volume10
Early online date2 Jul 2016
DOIs
Publication statusPublished - 1 Aug 2016

Keywords

  • Ovarian cancer
  • Fallopian tube
  • BRCA mutations
  • SOX2
  • Screening
  • Precancer

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