title: The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients.
abstract: OBJECTIVE
  We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients.
  
  
  METHODS
  In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays.
  
  
  RESULTS
  Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells.
  
  
  CONCLUSIONS
  Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Javier
authors.identifier: http://orcid.org/0000-0003-0377-6712
authors.initials: J
authors.lastname: Gayarre
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Kamieniak
authors.affiliation: Department of Pathology, Fundación Jiménez Díaz-IDC Salud, Madrid, Spain.
authors.forename: Alicia
authors.identifier: http://orcid.org/0000-0002-9534-8418
authors.initials: A
authors.lastname: Cazorla-Jiménez
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Muñoz-Repeto
authors.affiliation: Department of Genetics, Reproduction, and Fetal Medicine, IBIS, University Hospital Virgen del Rocio, CSIC, University of Seville, Seville, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
authors.affiliation: Medical Oncology Service, Oncologic Center Clara Campal, Madrid, Spain.
authors.forename: Jesús
authors.identifier: http://orcid.org/0000-0001-7731-3601
authors.initials: J
authors.lastname: García-Donas
authors.affiliation: Department of Oncology, Fundación Hospital Alcorcón, Alcorcon, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Hernando
authors.affiliation: Familial Cancer Unit and Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.identifier: http://orcid.org/0000-0002-6098-7746
authors.initials: L
authors.lastname: Robles-Díaz
authors.affiliation: Department of Oncology, Hospital General de Albacete, Albacete, Spain.
authors.forename: José M
authors.identifier: http://orcid.org/0000-0003-3892-8894
authors.initials: JM
authors.lastname: García-Bueno
authors.affiliation: Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain.
authors.forename: Teresa
authors.identifier: http://orcid.org/0000-0003-3490-3585
authors.initials: T
authors.lastname: Ramón Y Cajal
authors.affiliation: Breast Cancer Clinical Research Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Hernández-Agudo
authors.affiliation: Pathology and Translational Oncology Research Laboratories, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Heredia Soto
authors.affiliation: Medical Oncology Service, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Márquez-Rodas
authors.affiliation: Medical Oncology Service, Hospital Severo Ochoa, Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Echarri
authors.affiliation: Department of Internal Medicine, Hospital Severo Ochoa, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Lacambra-Calvet
authors.affiliation: Laboratory of Genetics, Hospital Donostia, San Sebastian, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sáez
authors.affiliation: Department of Obstetrics and Gynecology, Hospital Universitario Quirón-Dexeus, Barcelona, Spain.
authors.forename: Maite
authors.identifier: http://orcid.org/0000-0003-1631-1500
authors.initials: M
authors.lastname: Cusidó
authors.affiliation: Department of Medical Oncology, Hospital La Paz IdiPAZ, Madrid, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Redondo
authors.affiliation: Medical Oncology Service, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.identifier: http://orcid.org/0000-0002-3327-3246
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Pathology Research Laboratory, Department of Pathology, Hospital La Paz IdiPAZ, and Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-2183-3699
authors.initials: D
authors.lastname: Hardisson
authors.affiliation: Pathology and Translational Oncology Research Laboratories, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
authors.forename: Marta
authors.identifier: http://orcid.org/0000-0002-2463-1304
authors.initials: M
authors.lastname: Mendiola
authors.affiliation: Department of Pathology, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: José
authors.identifier: http://orcid.org/0000-0002-1612-8389
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.|Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain. mjgarcia@cnio.es.
authors.forename: María José
authors.identifier: http://orcid.org/0000-0002-2236-9912
authors.initials: MJ
authors.lastname: García
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C512380:GTF2H5 protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors
keywords: 6q24-26 Deletion; Cisplatin-Sensitivity; DNA Repair; GTF2H5; Ovarian Epithelial Cancer; Survival