Polymorphism Of XRCC1 Gene Influences Response To The Sensitivity Of Neoadjuvant Chemoradiotherapy In Patients With Advanced Gastric Cancer

Objectives:Neoadjuvant chemoradiotherapy(NCRT) can effectively decrease the tumor volume, improve the radical resection rate and anus preservation rate, as well as to reduce the postoperative local recurrence and prolong survival of patients with locally advanced rectal cancer(LARC), However, not all patients can benefit from NCRT. Some patients may be not sensitive to NCRT, thus not only losing the optimal opportunity of surgery, but also increasing the economic burden.Arg399Gln polymorphism in human X-ray repair cross complementing gene1(XRCC1) has been proved to be associated with the reponse to platinum-based chemotherapy in lung cancer and esophagus cancer. In this case, XRCC1 Arg399 Gln polymorphism may be a biological predictor of NCRT efficacy. By detecting the expression level of XRCC1 Arg399 Gln polymorphism in colorectal cancer patients and analyzing the correlations with the sensitivity and efficacy of NCRT, we could realize the significance of Arg399 Gln polymorphism in predicting the sensitivity of NCRT in patients with locally advanced rectal cancer. Methods:Clinical pathologic data of 64 patients with locally advanced colorectal cancer was collected. The Arg399 Gln polymorphism of XRCC1 was also tested through the peripheral blood. Patients enrolled got surgical resection after NCRT. The sensitivity of NCRT was evaluated through efficacy evaluation of CT and Dworak’s postoperative tumor regression grading(TRG). Clinicopathologic data and XRCC1 Arg399 Gln polymorphism were both analyzed through univariate analysis in order to find out significant associations with response to NCRT. Multiple logistic regression analysis was also operated to explore the independent influencing factors. By doing this, significant indicator of predicting the reponse to NCRT could be realized, which would be able to direct the individualized treatment of patients with LARC.Results:A total of 64 patients with locally advanced rectal cancer(cT3-4N0M0 or TxN+M0) was enrolled, in which 38 patients were males while 26 patients were females. The XRCC1 Arg399 Gln polymorphisms were all tested through peripheral blood in use of polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP), among which the number of wild homozygous genotype(GG) was 33, the heterozygosis mutation genotype(GA) 24 and the homozygous mutations genotype(AA) 7. The frequency of Arg399 Gln locus conforms to Hardy-Weinberg equilibrium(p=0.42), insuring the reliability of the clinical trial. In the evaluation of CT curative effect, 10 patients got a complete response(CR), and the number of partial response(PR), stable disease(SD), progress disease(PD) was 16, 24,14. In the system of Dworak’s postoperative tumor regression grading, the number of TRG4(pathologic complete response, pCR), TRG3, TRG2, TRG1 and TRG0 was 12, 17, 15, 12 and 10.In the univariate analysis concerning the association between clinicopathologic data, XRCC1 Arg399 Gln polymorphisms and response to NCRT according to the Dworak’s TRG standard, the clinical T stages(p=0.02), N stages(p=0.016) and pre-CEA levels(p=0.047) were significantly associated with the response to NCRT, as well as the XRCC1 Arg399 Gln polymorphisms(p=0.011). Patients with the wild homozygous genotype(GG) had better response to NCRT than those with heterozygosis mutation genotype(GA) or homozygous mutations genotype(AA). In the evaluation of CT curative effect, the clinical T stages, N stages, pre-CEA levels and XRCC1 Arg399 Gln polymorphisms were also significantly associated with the response to NCRT.In the analysis of multiple logistic regression, we found that clinical T stages(p=0.005) was the independent influencing factor to the response of NCRT. When having a lower clinical T stage, LARC patients with the wild homozygous genotype(GG) had better response to NCRT than those with heterozygosis mutation genotype(GA) or homozygous mutations genotype(AA). Conclusions:Clinical T stages, N stages, pre-CEA levels and XRCC1 Arg399 Gln polymorphisms were significantly associated with the response to NCRT of LARC. XRCC1 can be used as a biological indicator of predicting sensitivity of neoadjuvant chemoradiotherapy in patients with advanced colorectal cancer. Clinical T stages was the independent influencing factor. When having a lower clinical T stage, patients with the wild homozygous genotype(GG) of XRCC1 Arg399 Gln polymorphisms could benefit better response to NCRT of LARC.