DNA Repair Gene Polymorphisms Predict Favorable Clinical Outcome in Advanced Non–Small-Cell Lung Cancer

Aristea Kalikaki; Maria Kanaki; Helen Vassalou; John Souglakos; Alexandra Voutsina; Vassilis Georgoulias; Dimitris Mavroudis

Disclosures

Clin Lung Cancer. 2009;10(2):118-123. 

In This Article

Discussion

In the current study we examined whether polymorphisms in genes (GSTP1, GSTT1, GSTM1, ERCC1, XPD, XRCC1) related to the metabolism of cisplatin and DNA repair could be used as predictors of the clinical outcome of patients with advanced NSCLC treated with platinum-based chemotherapy.

Our findings demonstrate that NSCLC patients with the CC/CT genotypes in the ERCC1 118 polymorphism have a higher probability of response to platinum-based treatment than those with the TT genotype. Overall survival times of patients with the CC/CT genotypes were increased compared with those of the TT genotype (12.6 vs. 7.1 months); however, this difference was not statistically significant (P = .063) probably due to the small sample size of this study. In similar studies in NSCLC, better clinical outcome and improved survival have been linked to the C as well as the T alleles.[22,23,24] It has been previously reported that the synonymous N118N polymorphism affected mRNA and protein levels, thus leading to differential cisplatin sensitivity.[12] Nevertheless, a recent study in epithelial ovarian cancer failed to show an association between ERCC1 mRNA levels and codon 118 polymorphism. A possible explanation for this observation has proposed the C ERCC1 C8092A different translation rate of synonymous polymorphic codons that may affect ERCC1 protein levels and/or cotranslational protein folding, leading to a functionally different protein.[25,26]

In our study, the A allele of ERCC1 C8092A polymorphism was significantly associated with longer OS in the univariate and multivariate analysis. Moreover, a recent study also demonstrated that NSCLC patients carrying at least one 8092A allele presented a greater than two-fold increase in grade 3 or 4 gastrointestinal toxicity.[27] In our study, we failed to demonstrate a similar association; however, we could hypothesize that the C/A and A/A genotypes result in lower levels of DNA repair capacity, thus leading to higher efficacy of platinum-based treatment and increased toxicity. In contrast with our findings, Zhou et al. reported that any copies of the A allele were associated with shorter survival in stage III NSCLC patients. This discrepancy could be at-tributed to the different chemotherapy regimens used in the two studies as well as different patients' characteristics (tumor histology, stage of disease). The ERCC1 C8092A is located in the 3' untranslated region, which was found to be involved in translational repression of ERCC1 mRNA.[28] Nevertheless, further biochemical studies are required to clarify the effect of ERCC1 polymorphism on gene transcription and protein translation. Several studies have suggested that low levels of intratumoral ERCC1 expression were associated with improved survival after platinum-based chemotherapy; however, ERCC1 mRNA and pro-tein levels were not correlated.[29,30,31]

Interestingly, given the high linkage disequilibrium between the two ERCC1 polymorphisms, the presence of 2 ERCC1 polymorphic vari-ants (C8092A, A/A, C/A and N118N C/C, C/T) was independently associated with OS. However, there was no significant association be-tween the presence of 2 ERCC1 polymorphic variants and response to platinum-based treatment. We can postulate that linkage disequilibrium might occur between these polymorphisms and other possible relevant sites within the ERCC1 or other genes, and this may influence response to platinum-based treatment. It is likely that additional haplotype analyses could elucidate further the effect of genetic polymorphisms on response to platinum-based therapy.

The polymorphism Arg399Gln of XRCC1 has been associated with higher levels of DNA adducts, suggesting a deficient DNA repair func-tion.[15,32] XRCC1 is a scaffold factor involved in the repair of single-strand breaks following BER. Codon 399 in XRCC1 is located within a BRCT (BRCA1 C-terminus) domain which is believed to be a pro-tein-protein interface that interacts with poly(ADP-ribose) polymerase involved in BER.[33] Our results indicate that G/G and G/A genotypes of codon 399 polymorphism are favorable genotypes for survival of NSCLC patients receiving platinum-based chemotherapy. Our find-ings are consistent with other reports in NSCLC and CRC that provide evidence of a favorable effect of the codon 399 G/G genotype on overall survival.[21,34,35]

Our study has several limitations. First, this is a retrospective study, and although we adjusted for various clinical parameters (such as tumor histology and stage of disease) in our analyses, smoking status data were incomplete or missing and therefore were not adjusted in logistic and Cox regression models. Given the significant interactions between ERCC1 genotypes and smoking status in the risk of developing lung cancer, a potential confounding factor may exist.[36] Second, because of the relatively small patient population analyzed and the heterogeneity of both patients enrolled and treatment administered, our findings should be interpreted with caution and require further validation in subse-quent studies. However, despite these limitations, the data of this study contribute significant information on the prognostic and predictive value of these polymorphisms and may prove to be useful tools toward individualizing NSCLC treatment strategies.

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