2026-05-17T01:24:19Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/85352024-11-29T19:40:10Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
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
funder
Ovarian Cancer Action (Reino Unido)
funder
NIHR - Oxford Biomedical Research Centre (Reino Unido)
funder
National Institute for Health Research (Reino Unido)
funder
Experimental Cancer Medicine Centres
funder
Medical Research Council (Reino Unido)
funder
Wellcome Trust
funder
Cancer Research UK (Reino Unido)
2019-10-30T10:32:31Z
2019-10-30T10:32:31Z
2016-08-10
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
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.
eng
BRCA mutations
Fallopian tube
Ovarian cancer
Precancer
SOX2
Screening
Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies
journal article
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