title: Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies.
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 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.
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Karin
authors: K
authors: Hellner
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Fabrizio
authors: F
authors: Miranda
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Donatien
authors: D
authors: Fotso Chedom
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Sandra
authors: S
authors: Herrero-Gonzalez
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States.
authors: Daniel M
authors: DM
authors: Hayden
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States.
authors: Rick
authors: R
authors: Tearle
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK; University of Oxford, Gene Regulatory Networks in Development and Disease Laboratory, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, UK.
authors: Mara
authors: M
authors: Artibani
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Eli M
authors: EM
authors: Carrami
authors: University of Oxford, Gene Regulatory Networks in Development and Disease Laboratory, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, UK.
authors: Ruth
authors: R
authors: Williams
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Kezia
authors: K
authors: Gaitskell
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Samar
authors: S
authors: Elorbany
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Ruoyan
authors: R
authors: Xu
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Alex
authors: A
authors: Laios
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Petronela
authors: P
authors: Buiga
authors: Trinity College, University of Cambridge, Cambridge CB2 1TQ, UK.
authors: Karim
authors: K
authors: Ahmed
authors: Department of Histopathology, Oxford University Hospitals, Oxford OX3 9DU, UK.
authors: Sunanda
authors: S
authors: Dhar
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States.
authors: Rebecca Yu
authors: RY
authors: Zhang
authors: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Leticia
authors: L
authors: Campo
authors: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Kevin A
authors: KA
authors: Myers
authors: Histopathology Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: María
authors: M
authors: Lozano
authors: Biobank, Institut de Recerca Biomèdica Lleida (IRBLLEIDA), Lleida, Spain.
authors: María
authors: M
authors: Ruiz-Miró
authors: Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain.
authors: Sónia
authors: S
authors: Gatius
authors: Department of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain; MD Anderson international Foundation, Madrid, Spain.
authors: Alba
authors: A
authors: Mota
authors: Department of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain; MD Anderson international Foundation, Madrid, Spain.
authors: Gema
authors: G
authors: Moreno-Bueno
authors: Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain.
authors: Xavier
authors: X
authors: Matias-Guiu
authors: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors: Javier
authors: J
authors: Benítez
authors: Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Lorna
authors: L
authors: Witty
authors: Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Gil
authors: G
authors: McVean
authors: Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Simon
authors: S
authors: Leedham
authors: Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Ian
authors: I
authors: Tomlinson
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States; BGI-Shenzhen, Shenzhen, China.
authors: Radoje
authors: R
authors: Drmanac
authors: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK; Centre for Computational Biology, University of Birmingham, Edgbaston B15 2TT, UK.
authors: Jean-Baptiste
authors: JB
authors: Cazier
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States.
authors: Robert
authors: R
authors: Klein
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States.
authors: Kevin
authors: K
authors: Dunne
authors: Department of Experimental Therapeutics, M.D. Anderson Cancer Center, University of Texas, USA.
authors: Robert C
authors: RC
authors: Bast
authors: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors: Stephen H
authors: SH
authors: Kennedy
authors: Tumor Growth Control Group, Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors: Bassim
authors: B
authors: Hassan
authors: Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Stefano
authors: S
authors: Lise
authors: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain.
authors: María José
authors: MJ
authors: Garcia
authors: Complete Genomics, Inc., 2071 Stierlin Ct., Mountain View, CA 94043, United States; BGI-Shenzhen, Shenzhen, China.
authors: Brock A
authors: BA
authors: Peters
authors: Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, 1 South Parks Road, Oxford OX1 3TG, UK.
authors: Christopher
authors: C
authors: Yau
authors: University of Oxford, Gene Regulatory Networks in Development and Disease Laboratory, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, UK.
authors: Tatjana
authors: T
authors: Sauka-Spengler
authors: Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: ahmed.ahmed@obs-gyn.ox.ac.uk.
authors: Ahmed Ashour
authors: AA
authors: Ahmed
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005187:Fallopian Tubes / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D061705:Image-Guided Biopsy; D010535:Laparoscopy; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D011230:Precancerous Conditions; D012045:Regulatory Sequences, Nucleic Acid; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D055748:SOXB1 Transcription Factors
keywords: BRCA mutations; Fallopian tube; Ovarian cancer; Precancer; SOX2; Screening