J Gynecol Oncol. 2016 Jan;27(1):e7. English. Original Article. https://doi.org/10.3802/jgo.2016.27.e7
Ramon y Cajal T
Heredia Soto V
Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. firstname.lastname@example.org
Department of Pathology, Fundacion Jimenez Diaz-IDC Salud, Madrid, Spain.
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.
Medical Oncology Service, Oncologic Center Clara Campal, Madrid, Spain.
Department of Oncology, Fundacion Hospital Alcorcon, Alcorcon, Spain.
Familial Cancer Unit and Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
Department of Oncology, Hospital General de Albacete, Albacete, Spain.
Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain.
Breast Cancer Clinical Research Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
Pathology and Translational Oncology Research Laboratories, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
Medical Oncology Service, Instituto de Investigacion Sanitaria Gregorio Maranon, Universidad Complutense, Madrid, Spain.
Medical Oncology Service, Hospital Severo Ochoa, Madrid, Spain.
Department of Internal Medicine, Hospital Severo Ochoa, Madrid, Spain.
Laboratory of Genetics, Hospital Donostia, San Sebastian, Spain.
Department of Obstetrics and Gynecology, Hospital Universitario Quiron-Dexeus, Barcelona, Spain.
Department of Medical Oncology, Hospital La Paz IdiPAZ, Madrid, Spain.
Medical Oncology Service, Hospital 12 de Octubre, Madrid, Spain.
Pathology Research Laboratory, Department of Pathology, Hospital La Paz IdiPAZ, and Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
Department of Pathology, Hospital Universitario Ramon y Cajal, Madrid, Spain.
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 < or = 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.
CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.