| 摘要: | Introduction
Oral cancer (OC) poses a serious public health burden, with high morbidity and mortality globally. Over 90% of OC are oral squamous cell carcinoma (OSCC). Potentially malignant oral disorders (PMODs) are highly transformative, contributing to the OC incidence. The pathology of these oral tumors involves multiple and complex biological processes, mediated by both endogenous and exogenous factors that include reactive oxygen species (ROS), genetic and lifestyle factors such as alcohol drinking betel nut chewing and cigarette smoking. The diagnosis and treatment of OSCC have improved over the past decades, however, this has not brought about a remarkable reduction in the mortality. This phenomenon may partly be attributed to the fact that many OSCC cases are diagnosed at an advanced stage, decreasing their likelihood of survival. Evidence has also shown that single nucleotide polymorphisms (SNPs) in DNA repair genes may play a major role in the sensitivity of cancer cells to radiochemotherapy. Thus, we investigate the association between inherent and lifestyle factors on PMODs risks and prognosis of OSCC.
Methods
The study uses a multidisciplinary approach combining two study designs. The case-control studies used 709 male subjects (224 cases: 485 controls) to study the association between polymorphisms in MTHFR gene and oxidative stress biomarkers on the risk of PMOD development. The retrospective cohort studies examined the association between polymorphisms in DNA repair genes and prognosis of oral OSCC in 319 male patients receiving concurrent chemotherapy (CCRT). MTHFR C677T and A1298C polymorphisms were determined using polymerase chain reaction and restriction fragment length polymorphism whereas the Sequenom iPLEX MassARRAY system was used for genotyping variants in the DNA repair genes. The measurements of plasma 8-hydroxy-2’-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO) were obtained by enzyme-linked immunosorbent assay. Multivariate logistic regression models were used to assess risk factors for PMODs. The Kaplan–Meier curves and multivariate Cox proportional hazard regression models were used to identify factors associated with survival.
Results
The results indicate the T-allele in MTHFR C677T polymorphism may be associated with reduced risk for PMODs (odds ratio [OR] = 0.62, 95% confidence interval [CI] = 0.44-0.86), and the 677T/1298A TA haplotype was associated with a decreased risk of PMODs (OR = 0.56, 95% CI = 0.40-0.80). Increased plasma 8-isoprostane (8-ISO) levels are associated with increased risk for PMODs (OR = 1.71, 95% CI = 1.12–2.63; p = 0.013). This positive association was stronger among patients with PMOD subtype of leukoplakia (OR = 1.94, 95% Cl = 1.24–3.06; p = 0.004). The DNA repair SNPs XPC rs2228000 TT genotype (hazard ratio [HR] = 1.81, 95% CI = 0.99–3.29), MLH1 rs1800734 GG genotype (HR = 0.52, 95% CI = 0.27–1.01; p=0.054), XRCC1 rs1799782 CT+TT genotypes (HR = 0.65, 95% CI = 0.43–0.99; p = 0.044) and APEX1 rs1760944 GG genotype (HR = 1.64, 95% CI = 1.00–2.70; p = 0.050) were associated with overall survival. In addition, the genetic variants ERCC5 rs17655 CC genotypes (HR = 1.54, 95% CI = 1.03–2.29), ERCC1 rs735482 CC genotypes (HR = 1.65, 95% CI = 1.06–2.58), MSH2 rs3732183 GG genotype (HR = 0.45; 95% CI = 0.22–0.96; p=0.039), MLH1 rs1800734 GG genotype (HR = 0.49, 95% CI = 0.26–0.92; p=0.028), MUTYH rs3219489 GG genotype (HR = 2.01, 95% CI = 1.31–3.10; p = 0.002), and XRCC2 rs2040639 AA genotype (HR = 0.55, 95% CI=0.31–0.98; p=0.042) were associated with disease-free survival in OSCC patients receiving CCRT.
Conclusions
Our findings indicate that the MTHFR C677T T-allele and increased plasma 8-ISO level are important factors in PMOD development. In addition, DNA repair variants XPC rs2228000, ERCC5 rs17655, ERCC1 rs735482, MSH2 rs3732183, MLH1 rs1800734, XRCC1 rs1799782, APEX1 rs1760944, MUTYH rs3219489 and XRCC2 rs2040639 affect survival of patients with advanced OSCC. These SNPs may serve as prognostic markers for OSCC prognosis. These findings may require confirmation in studies of larger samples or other ethnic populations. |
