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

• Gayarre J
• Kamieniak
• Cazorla-Jimenez A
• Munoz-Repeto I
• Borrego S
• Garcia-Donas J
• Hernando S
• Robles-Diaz L
• Garcia-Bueno JM
• Ramon y Cajal T
• Hernandez-Agudo E
• Heredia Soto V
• Marquez-Rodas I
• Echarri MJ
• Lacambra-Calvet C
• Saez R
• Cusido M
• Redondo A
• Paz-Ares L
• Hardisson
• Mendiola M
• Palacios J
• Benitez J
• Garcia MJ

• KMID: 2360237
• DOI: http://doi.org/10.3802/jgo.2016.27.e7

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