Abstract
Purpose ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs) in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients.Experimental DesignWe genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986) and ERCC2 SNPs (rs13181 and rs1799793) in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes.ResultsWe found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P = 0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P = 0.004). In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P = 0.025), compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986) had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P = 0.011), compared with the common haplotype G-T-G.Conclusion ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.
Highlights
Gastric cancer is the second leading cause of cancer deaths, ranking the fourth most common cancer in the world, with approximately 989,600 new cases and 738,000 deaths every year [1]
We found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P = 0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [hazards ratios (HRs)] 2.13; 95% confidence intervals (95% CIs), 1.28 to 3.56; P = 0.004)
Patients with any one of the three unfavorable genotypes (i.e. excision-repair cross-complementing complementation group 1 (ERCC1) rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P = 0.025), compared with those without any unfavorable genotypes
Summary
Gastric cancer is the second leading cause of cancer deaths, ranking the fourth most common cancer in the world, with approximately 989,600 new cases and 738,000 deaths every year [1]. The TNM (tumor/nodule/metastasis) stage is the most acceptable measurement for evaluating effects of therapies and prognosis; it is not uncommon that patients with the same tumor stage and treatment may have various outcomes. For surgeons and oncologists, it would be helpful to improve the accuracy in predicting clinical outcome by identifying genetic makers that could facilitate individualized anticancer therapy, post-operational adjunctive treatment and follow-up strategies. Individual differences or variations in response to chemotherapies or radiotherapies are likely due to their different genetic make-ups, leading to different clinical outcomes. Single nucleotide polymorphisms (SNPs) are the most commonly investigated genetic variation that may influence patients’ clinical outcomes [3,4,5]
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