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A nuclear polymorphism at the 8q24 region is associated with improved survival time and chemo-response in high-grade serous ovarian cancer.

ABSTRACT: The 8q24 chromosomal region is strongly associated with an increased risk of ovarian cancer. One single nucleotide polymorphism that is associated with ovarian cancer in this region is rs6983267, located within the long non-coding RNA colon cancer associated transcript 2 (CCAT2). The aim of the present study was to assess the association between rs6983267 and clinical outcomes in patients with high-grade serous ovarian cancer (HGSOC). The present retrospective genetic association study utilized Sanger sequencing to determine the genotype at the rs6983267 locus (GG, GT, TT) in 98 patients with HGSOC. Survival time and chemotherapy responses between patients were compared with the TT genotype and patients with a genotype containing a G allele (GT, GG). Survival analyses were performed using Cox proportional hazard ratio analysis. Association with chemo-response was performed using a logistic regression. The results revealed that patients with HGSOC and the TT genotype at the rs6983267 locus had improved survival time compared with patients with genotypes containing a G allele [hazard ratio=0.59; 95% confidence interval (CI), 0.36-0.97; P=0.039] and were significantly associated with International Federation of Gynecology and Obstetrics stage [odds ratio (OR)=5.34; 95% CI, 1.50-22.62; P=0.014] and positive chemo-response (OR=4.51; 95% CI, 1.40-18.00; P=0.018). In summary, patients with HGSOC and the TT genotype at the rs6983267 locus had improved survival time compared with those with a G allele, despite being associated with more advanced disease; this was possibly due to an improved response to chemotherapy.

SUBMITTER: Ikoma D

PROVIDER: S-EPMC8371958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveWe 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.MethodsIn 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.ResultsLow 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.ConclusionLow levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.

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A nuclear polymorphism at the 8q24 region is associated with improved survival time and chemo-response in high-grade serous ovarian cancer.

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