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oai:repisalud.isciii.es:20.500.12105/85352024-11-29T19:40:10Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Hellner, Karin author Miranda, Fabrizio author Fotso Chedom, Donatien author Herrero-Gonzalez, Sandra author Hayden, Daniel M author Tearle, Rick author Artibani, Mara author KaramiNejadRanjbar, Mohammad author Williams, Ruth author Gaitskell, Kezia author Elorbany, Samar author Xu, Ruoyan author Laios, Alex author Buiga, Petronela author Ahmed, Karim author Dhar, Sunanda author Zhang, Rebecca Yu author Campo, Leticia author Myers, Kevin A author Lozano, María author Ruiz-Miró, María author Gatius, Sónia author Mota, Alba author Moreno-Bueno, Gema author Matias-Guiu, Xavier author Benitez, Javier author Witty, Lorna author McVean, Gil author Leedham, Simon author Tomlinson, Ian author Drmanac, Radoje author Cazier, Jean-Baptiste author Klein, Robert author Dunne, Kevin author Bast, Robert C author Kennedy, Stephen H author Hassan, Bassim author Lise, Stefano author Garcia, María José author Peters, Brock A author Yau, Christopher author Sauka-Spengler, Tatjana author Ahmed, Ahmed Ashour author 2016-08-10 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. EBioMedicine. 2016 ;10:137-49. 10.1016/j.ebiom.2016.06.048 2352-3964 23523964 EBioMedicine 27492892 http://hdl.handle.net/20.500.12105/8535 BRCA mutations Fallopian tube Ovarian cancer Precancer SOX2 Screening Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies