| Backgrouds and ObjectivesThe incidence and mortality of colorectal cancer show increasing tendency worldwide. It was estimated that the new cases in 2007 would be approximate 1 200 000 and the death cases would be 630 000, a total increase of 27% and 28% respectively, compared with the figures in 2000. While the incidence tends to be low in China, however, during the past decades, there has been remarkable increase in the incidence of colorectal cancer. According to the Chinese National Cancer Database of 2003, colorectal cancer is one of the three cancers with most rapidly increasing incidence in the country between 1991 and 2003, and finally it ranks the third commonest malignant tumor, just behind lung cancer and female breast cancer.Most common human cancers, including colorectal cancer, have a multifactorial etiology involving complex interplay of genetic susceptibility and environmental exposures. It is widely accepted that environmental factors play key roles in the development and progression of colorectal cancer. The proportion of colorectal cancer attributed to environmental factors has been estimated to be above 70%. Diet and lifestyles are considered to be intimately associated with colorectal cancer risk. However, exposure to the same environmental factors, not everyone will develop colorectal cancer. Genetic polymorphisms have a key role in individual predisposition to colorectal cancer. It was found that progressive inhibition or evasion of apoptosis has been found during the transformation of colorectal epithelium to carcinoma, indicating that dysfunction of apoptosis has an important role in colorectal tumorigenesis. Apoptosis, which is mainly mediated by caspase family, play an important role in the maintenance of tissue homeostasis and inhibition of tumor formation in organisms. Apoptotic capacity is a subject of significant interindividual variations, which are largely attributed to hereditary traits. Genetic polymorphisms located within cell death genes may influence apoptosis activity. Low activity of apoptosis would favor cancer development because of the failure to eliminate cellular clones carrying DNA damage and propensity to inflammation.In order to explore the effect of environmental exposure, genetic polymorphisms in caspase mediated apoptosis pathway as well as the interactions between selected genes and environmental factors on colorectal cancer risk, a population-based case-control study was conducted in Jiashan County, Zhejiang Province, of which both field questionnaire survey and laboratory genotyping detection were adopted.Materials and MethodsFrom May 1989 to April 1990, a prospective cohort study based on a colorectal cancer survey was initiated in Jiashan County, Zhejiang Province, China. Subsequently, a cancer surveillance and registry system covering the whole population in Jiashan County was established to report new patients with various cancers. Between 2002 and 2008,498 CRC cases had been recruited in this study, based on the surveillance and registry system. All of the CRC cases were confirmed by histological diagnosis. However, patients with other malignant disease in their medical history were excluded from this study. Simultaneously,838 controls without the history of cancer were selected randomly from the corresponding population. All participants were Han Chinese residents.During the field survey, a structured questionnaire, including demographic characteristics, personal habits (cigarette smoking, alcohol drinking, etc) and health factors (family history of cancer at any site including all first- and second-degree relatives of both genders, medical and dietary history, etc) and 5 ml venous blood sample were collected from each subject. A combinative strategy of functional genetic polymorphisms and tagging singlenucleotide polymorphisms was applied to the selection of susceptible biomarker in apoptosis mediated pathway. Tagging single-nucleotide polymorphisms were selected by searching Han Chinese data from the HapMap project using the Tagger program. The genomic DNA was extracted from peripheral blood samples using modified salting-out procedure. For determination of the selected genetic polymorphisms, Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay was performed. Multiple statistical methods were used when estimating the major effect and the interactive effect of environmental factors and the genetic polymorphisms involved in caspase mediated apoptosis pathway, including Logistic regression, stratified analysis, crossover analysis, Multifactor Dimensionality Reduction (MDR) analysis and Classification And Regression Tree (CART) analysis.ResultsThe demographic characteristics and family history of cancer did not differ significantly between cases and controls. There was no association between variables concerning drinking and colorectal cancer risk. Smokers without smoke inhalation had lower risk of suffering from colorectal cancer compared with smoke inhalation smokers (OR=0.41, 95%CI:0.24-0.70), while nonsmokers did not show significant difference in colorectal cancer risk when compared with smoke inhalation smokers (OR= 1.22,95%CI:0.86-1.72). An increased risk of colorectal cancer was indicated by the higher daily cigarette consumption of smoking. But the association between the accumulated cigarette consumption and colorectal cancer risk was not significant. Tea drinking could significantly decrease the colorectal cancer risk about 51%(OR=0.49,95%CI: 0.36-0.66). Significant dose-response relationships were found for the average amount of tea consumed by year (P trend=0.01). The reduction in risk was most evident among those who consume tea above 3kg a year (OR=0.31,95%CI:0.18-0.54). Diet showed strong association with colorectal cancer risk. Individuals who consumed red meat more than 19.45kg every year, has a significant 36% decreased risk of colorectal cancer (OR=0.64,95%CI:0.45-0.91), compared with individuals in the lowest category. Higher chicken consumption showed a protective effect on colorectal cancer risk. While source-boiled fish has a significantly positive association with colorectal cancer. The risk of suffering colorectal cancer of people who consumed source-boiled fish more than 7.2kg one year is 1.64 times higher than the reference group (95%CI:1.17-2.30). In this study, totally 12 genetic polymorphisms of 5 genes involved in caspase mediated apoptosis pathway were analyzed, of which eight were potential functional genetic polymorphisms and four are tagging single nucleotide polymorphisms. It was found that Caspase3 rs4647693 AA genotype had a protective effect on susceptibility to colorectal cancer (OR=0.50,95%CI:0.26-0.95). The carriers with haplotype A-Ins in Caspase8 rs3769818 and rs3834129 showed an increased risk of rectal cancer (OR=1.28,95%CI: 1.00-1.63). Among the non-drinkers, it was found that compared with Caspase8 rs3769818 GG genotype carriers, the GA genotype carriers had a 32% increased risk of colorectal cancer (OR=1.32,95%CI:1.00-1.74); the AA genotype of rs4647693 in the Caspase3 gene was associated with decreased risk compared with homozygotes of the major alleles (OR=0.42,95%CI:0.19-0.93); the rs2696056 GC genotype in Caspase3 gene was significantly associated with increased cancer risk compared with the GG genotype (OR=1.42,95%CI:1.02-1.96). Crossover analysis suggested that Caspase8 rs3769818 had combined effects with Caspase3 rs4647693 GG risk genotype. Combinative effect was also observed between Caspase8 rs3769818 and Caspase3 rs12108497. However, neither of the interactions between the SNPs had statistical significance.High order interaction models were explored by MDR and CART methods. Both of the two data-mining methods indicated that environmental factors played an important role in the colorectal cancer risk. The selected genetic polymorphisms may further modify the colorectal cancer risk but not as a main effect.ConclusionsOur findings verified the important influence of environmental factors on CRC risk. Caspase3 rs4647693 has an independent effect on colorectal cancer risk with recessive model. Further studies with large sample size are warranted to validate our findings.
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