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

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2016
Author
Hellner, Karin
Miranda, Fabrizio
Fotso Chedom, Donatien
Herrero Gonzalez, Sandra
Hayden, Daniel M.
Tearle, Rick
Artibani, Mara
KaramiNejadRanjbar, Mohammad
Williams, Ruth
Gaitskell, Kezia
Elorbany, Samar
Xu, Ruoyan
Laios, Alex
Buiga, Petronela
Ahmed, Karim
Dhar, Sunanda
Yu Zhang, Rebecca
Campo, Leticia
Myers, Kevin A.
Lozano, María
Ruiz Miró, Maria
Gatius Calderó, Sònia
Mota, Alba
Moreno Bueno, Gema
Matias-Guiu, Xavier
Benítez, Javier
Witty, Lorna
McVean, Gil
Leedham, Simon
Tomlinson, Ian
Drmanac, Radoje
Cazier, Jean Baptiste
Klein, Robert
Dunne, Kevin
Bast Jr, Robert C.
Kennedy, Stephen H.
Hassan, Bassim
Lise, Stefano
Garcia, María José
Peters, Brock A.
Yau, Christopher
Sauka-Spengler, Tatjana
Ashour Ahmed, Ahmed
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Hellner, Karin; Miranda, Fabrizio; Fotso Chedom, Donatien; Herrero Gonzalez, Sandra; Hayden, Daniel M.; Tearle, Rick; ... Ashour Ahmed, Ahmed. (2016) . Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: discovery and validation studies. EBioMedicine, 2016, vol. 10, p. 137-149. https://doi.org/10.1016/j.ebiom.2016.06.048.
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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.
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http://hdl.handle.net/10459.1/58040
DOI
https://doi.org/10.1016/j.ebiom.2016.06.048
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EBioMedicine, 2016, vol. 10, p. 137-149
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cc-by (c) Hellner et al., 2016
Except where otherwise noted, this item's license is described as cc-by (c) Hellner et al., 2016