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dc.contributor.authorHellner, Karin
dc.contributor.authorMiranda, Fabrizio
dc.contributor.authorFotso Chedom, Donatien
dc.contributor.authorHerrero Gonzalez, Sandra
dc.contributor.authorHayden, Daniel M.
dc.contributor.authorTearle, Rick
dc.contributor.authorArtibani, Mara
dc.contributor.authorKaramiNejadRanjbar, Mohammad
dc.contributor.authorWilliams, Ruth
dc.contributor.authorGaitskell, Kezia
dc.contributor.authorElorbany, Samar
dc.contributor.authorXu, Ruoyan
dc.contributor.authorLaios, Alex
dc.contributor.authorBuiga, Petronela
dc.contributor.authorAhmed, Karim
dc.contributor.authorDhar, Sunanda
dc.contributor.authorYu Zhang, Rebecca
dc.contributor.authorCampo, Leticia
dc.contributor.authorMyers, Kevin A.
dc.contributor.authorLozano, María
dc.contributor.authorRuiz Miró, Maria
dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorMota, Alba
dc.contributor.authorMoreno Bueno, Gema
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorBenítez, Javier
dc.contributor.authorWitty, Lorna
dc.contributor.authorMcVean, Gil
dc.contributor.authorLeedham, Simon
dc.contributor.authorTomlinson, Ian
dc.contributor.authorDrmanac, Radoje
dc.contributor.authorCazier, Jean Baptiste
dc.contributor.authorKlein, Robert
dc.contributor.authorDunne, Kevin
dc.contributor.authorBast Jr, Robert C.
dc.contributor.authorKennedy, Stephen H.
dc.contributor.authorHassan, Bassim
dc.contributor.authorLise, Stefano
dc.contributor.authorGarcia, María José
dc.contributor.authorPeters, Brock A.
dc.contributor.authorYau, Christopher
dc.contributor.authorSauka-Spengler, Tatjana
dc.contributor.authorAshour Ahmed, Ahmed
dc.description.abstractCurrent 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.ca_ES
dc.description.sponsorshipThis work is funded by the Medical Research Council (H8RSRS00), Ovarian Cancer Action (HER00070), the Oxford Biomedical Research Centre, the National Institute for Health Research (HJRWAC05) and the Experimental Cancer Medicine Centre. MJG is recipient of a research contract from the Instituto de Salud Carlos III of the Ministerio Español de Sanidad y Consumo (Miguel Servet tipo II Program, CPII 13-00047). C.Y. acknowledges the support of an MRC New Investigator Research Grant (Ref No. MR-L001411-1) and the Wellcome Trust Core Award Grant Number 090532-Z-09-Z.ca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofEBioMedicine, 2016, vol. 10, p. 137-149ca_ES
dc.rightscc-by (c) Hellner et al., 2016ca_ES
dc.subjectOvarian cancerca_ES
dc.subjectFallopian tubeca_ES
dc.subjectBRCA mutationsca_ES
dc.titlePremalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: discovery and validation studiesca_ES

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