Role of the RAD51 G172T polymorphism in the clinical outcome of cervical cancer patients under concomitant chemoradiotherapy

Abstract

Introduction: Cervical cancer is one of the most common cancers diagnosed in women worldwide. Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. The RAD51 protein is required for meiotic and mitotic recombination and plays a central role in homology-dependent recombinational repair of double-strand breaks (DSBs). Given the functional relevance of the DNA repair system on carcinogenesis, potential associations between genetic polymorphisms of DNA repair genes, cancer risk and response to therapy have been intensively evaluated. This is the first study evaluating the role of the RAD51 G172T genetic variants in cancer prognosis and clinical outcome of cervical cancer patients. Material and methods: We analyzed RAD51 G172T polymorphism genotypes in cervical cancer patients who underwent a platinum-based chemotherapy in combination with radiotherapy. Genotyping was performed by Taqman™ Allelic Discrimination methodology. Results and discussion: Concerning the overall survival rates found using Kaplan-Meier method and Log Rank Test, we observed that the mean survival rates were statistically different according to the patients RAD51 genotypes. The group of patients carrying the T allele present a higher mean survival rate than the other patients (102.3 months vs. 86.4 months, P = 0.020). Using the Cox regression analysis, we found an increased overall survival time for T-carrier patients, when compared with GG genotype, with tumor stage, age and presence of lymph nodes as covariates [hazard ratio (HR), 0.373; 95% CI, 0.181-0.770; P = 0.008]. Among patients (n = 193), RAD51 genotype frequency distributions were not under the influence of clinicopathologic characteristics, namely, treatment response (P = 0.508), recurrence (P = 0.150) and tumor stage (P = 0.250). Conclusions: This is the first study evaluating the role of the RAD51 G172T genetic variants in cancer prognosis and clinical outcome of cervical cancer patients. Our results indicate an influence of the RAD51 genetic variants in overall survival of cervical cancer. Thereby, RAD51 G172T genotypes may provide additional prognostic information in cervical cancer patients who underwent cisplatin-based chemotherapy in combination with radiotherapy.

Base excision repair pathway:PARP1genotypes as modulators of therapy response in cervical cancer patients

“…Previous studies have shown that therapy response can vary significantly among patients due to interindividual variations of DNA repair activity caused by the presence of genetic alterations in DNA repair genes which results in DNA repair deficiency and hence with chemoradiotherapy sensitization (Nogueira et al, 2012, de las Penas et al, 2006, Shi et al, 2012, Chung et al, 2006. Because of the importance of this process in determining sensitivity and resistance, components of the DNA damage repair pathways have been studied with regard to genetic variation and response to therapy (Hildebrandt et al, 2009).…”

Equivocal Association of RAD51 Polymorphisms with Risk of Esophageal Squamous Cell Carcinoma in a Chinese Population

“…The mutation of this gene may reverse the risk of cancers. Many documents have reported the association of RAD51 genetic factors with human cancers (Poplawski et al, 2006;Lu et al, 2007;Gresner et al, 2012;Nogueira et al, 2012).…”

“…It is located on the human chromosome 15q15.1, which contains 10 exons and encodes a protein with 339 amino acids (Lu et al, 2007;Nogueira et al, 2012). RAD51 is highly polymorphic: It has more than 100 SNPs, some of which have been suggested to contribute to cancers the risk of variable (Poplawski et al, 2006;Lu et al, 2007;Nogueira et al, 2012;Gresner et al, 2012).…”

“…It is located on the human chromosome 15q15.1, which contains 10 exons and encodes a protein with 339 amino acids (Lu et al, 2007;Nogueira et al, 2012). RAD51 is highly polymorphic: It has more than 100 SNPs, some of which have been suggested to contribute to cancers the risk of variable (Poplawski et al, 2006;Lu et al, 2007;Nogueira et al, 2012;Gresner et al, 2012). Several studies showed that rs1801320 (the G135C polymorphism) was associated with susceptibility to human cancers, such as breast (Romanowicz-Makowska et al, 2011) , colorectal (Krupa et al, 2011) and head and neck cancer (Sliwinski et al, 2010).…”

Ovarian cancer and DNA repair: DNA ligase IV as a potential key

“…Polymorphisms in genes involved in DNA repair could result in variations in efficacy and accuracy of DNA repair enzymes and consequently significantly affect the toxicity, effectiveness and therapy outcome. By their role in therapy response, genetic polymorphisms in these genes can influence the patient's survival and be useful as prognostic and predictive markers in cancer [40][41][42][43] . Moreover, with the development of DDR protein inhibitors for cancer treatment, research on targeting molecular pathways, such as DNA repair, is becoming one of the most important areas in clinical oncology [43][44][45][46][47][48] .…”