J Gynecol Oncol.  2016 Jan;27(1):e7. 10.3802/jgo.2016.27.e7.

The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients

Affiliations
  • 1Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. mjgarcia@cnio.es
  • 2Department of Pathology, Fundacion Jimenez Diaz-IDC Salud, Madrid, Spain.
  • 3Department of Genetics, Reproduction, and Fetal Medicine, IBIS, University Hospital Virgen del Rocio, CSIC, University of Seville, Seville, Spain.
  • 4Biomedical Network Research Centre on Rare Diseases (CIBERER), Madrid, Spain.
  • 5Medical Oncology Service, Oncologic Center Clara Campal, Madrid, Spain.
  • 6Department of Oncology, Fundacion Hospital Alcorcon, Alcorcon, Spain.
  • 7Familial Cancer Unit and Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
  • 8Department of Oncology, Hospital General de Albacete, Albacete, Spain.
  • 9Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain.
  • 10Breast Cancer Clinical Research Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  • 11Pathology and Translational Oncology Research Laboratories, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain.
  • 12Medical Oncology Service, Instituto de Investigacion Sanitaria Gregorio Maranon, Universidad Complutense, Madrid, Spain.
  • 13Medical Oncology Service, Hospital Severo Ochoa, Madrid, Spain.
  • 14Department of Internal Medicine, Hospital Severo Ochoa, Madrid, Spain.
  • 15Laboratory of Genetics, Hospital Donostia, San Sebastian, Spain.
  • 16Department of Obstetrics and Gynecology, Hospital Universitario Quiron-Dexeus, Barcelona, Spain.
  • 17Department of Medical Oncology, Hospital La Paz IdiPAZ, Madrid, Spain.
  • 18Medical Oncology Service, Hospital 12 de Octubre, Madrid, Spain.
  • 19Pathology Research Laboratory, Department of Pathology, Hospital La Paz IdiPAZ, and Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain.
  • 20Department of Pathology, Hospital Universitario Ramon y Cajal, Madrid, Spain.

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 < 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.

Keyword

Cisplatin-Sensitivity; DNA Repair; GTF2H5; Ovarian Epithelial Cancer; Survival; 6q24-26 Deletion

MeSH Terms

Adult
Aged
Aged, 80 and over
Biomarkers, Tumor/biosynthesis/genetics
Cystadenocarcinoma, Serous/*genetics/metabolism/pathology
Female
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Middle Aged
Neoplasm Grading
Neoplasm Proteins/biosynthesis/genetics
Neoplasms, Glandular and Epithelial/*genetics/metabolism/pathology
Ovarian Neoplasms/*genetics/metabolism/pathology
Prognosis
Transcription Factors/biosynthesis/*genetics
Tumor Cells, Cultured
Biomarkers, Tumor
Neoplasm Proteins
Transcription Factors
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