ABSTRACT
We analyzed associations of polymorphic markers of DNA repair genes (XRCC1, ERCC2), cell cycle control genes (TP53, MDM2, and CDKN1A), methylation of promoter region, and mutation 5382insC of BRCA1 gene in ovarian cancer with effectiveness of platinumbased chemotherapy assessed by the median of progression-free survival time for markers of DNA repair genes and by relapse risk for all studied markers. An increase in the median of progression-free survival time for carriers of the Gln allele (Ñ=0.025) and Gln/Gln genotype (Ñ=0.022) of the Gln399Arg XRCC1 was observed during the 19-months period after chemotherapy. In carriers of C/C genotype of 5382insC mutation of BRCA1 gene (n=6), no relapses were observed (Ñ=0.035), while 17 of 49 patients without this mutation developed relapses. Of 14 patients with BRCA1 gene function inactivation due to promoter methylation or the presence of the C/C genotype of 5382insC, one relapse was observed (p=0.033). Multivariate analysis revealed an association of markers of the XRCC1, TP53, MDM2 genes, BRCA1 gene inactivation, and type of surgery with the risk of relapse during the follow-up period up to 19 months after the end of chemotherapy (Ñ≤0.0007).
Subject(s)
Biomarkers, Tumor/genetics , Neoplasm Proteins/genetics , Neoplasm Recurrence, Local/genetics , Ovarian Neoplasms/genetics , Platinum Compounds/therapeutic use , Adenocarcinoma, Clear Cell/diagnosis , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/genetics , Adenocarcinoma, Clear Cell/mortality , Adult , Aged , Antineoplastic Agents/therapeutic use , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , Biomarkers, Tumor/metabolism , Carcinoma, Endometrioid/diagnosis , Carcinoma, Endometrioid/drug therapy , Carcinoma, Endometrioid/genetics , Carcinoma, Endometrioid/mortality , Cell Cycle/genetics , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cystadenocarcinoma, Serous/diagnosis , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/genetics , Cystadenocarcinoma, Serous/mortality , DNA Repair , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Mutation , Neoplasm Proteins/metabolism , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/mortality , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/mortality , Progression-Free Survival , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , X-ray Repair Cross Complementing Protein 1/genetics , X-ray Repair Cross Complementing Protein 1/metabolism , Xeroderma Pigmentosum Group D Protein/genetics , Xeroderma Pigmentosum Group D Protein/metabolismABSTRACT
We studied the association of polymorphic markers of cell cycle control genes (Arg72Pro of the TP53 gene, T(-410)G of the MDM2 gene, and Ser31Arg of the CDKN1A gene) in ovarian cancer and progression-free survival following platinum-based chemotherapy. Tumor tissue samples obtained from 49 patients who had undergone chemotherapy were examined. Patients received standard platinum-based chemotherapy and were observed until disease progression. Polymorphic markers of genes were evaluated by PCR-RFLP and real-time PCR. In patients carrying the G allele of the T(-410)G marker of the MDM2 gene, a decreasing trend was observed in median progression-free survival. An increase in the median progression-free survival was observed in carriers of the Pro allele of the TP53 gene (p=0.045). Furthermore, a stronger association was noted with carriers of the minor Pro/Pro homozygous genotype relative to the Arg/Arg genotype (p=0.007). In the subgroup of patients who underwent optimal or complete cytoreductive surgery, carriage of the minor Arg allele of the Ser31Arg marker (CDN1A gene) was associated with a decrease in the median progression-free survival time (p=0.004).
