| 摘要: | Introduction
Lynch syndrome is a germline mutation in mismatch repair (MMR) genes and a predisposing factor for CRC. Risk factors, such as smoking, physical activity, tea consumption, alcohol consumption, meat intake, fruits consumption and genetic polymorphism of MMR genes were reported to be associated with CRC in Lynch syndrome carriers. In contrast, TP53 Arg72Pro is one of the important tumour suppressor genes which play a crucial role of modulating genes that govern defences against cancer development by inhibition of the cell cycle, angiogenesis, cellular senescence, and brings about apoptosis.
Objectives
The aim of this retrospective cohort study was to investigate risk factors that are associated with CRC in individuals with MLH1 and MSH2 germline mutation and also to determine whether genetic polymorphisms can interact with life style factor to modify the risk of CRC in Taiwan.
Methods
In total, 303 MLH1 and MSH2 germline mutation carriers were identified from the Amsterdam II criteria family registry provided by the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. Information on sociodemographic characteristics, lifestyle factors, dietary factors, and medical history was obtained using a structured questionnaire. Genetic polymorphisms were analysed by Sequenom iPLEX MassArray platform. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) to determine the association between the risk factors, genetic polymorphisms and CRC development. Multiplicative interaction between genetic polymorphisms and lifestyle factors were also evaluated using a Cox proportional hazard model. A robust sandwich covariance estimation model was used to evaluate family dependence.
Results
Among the total cohort, subjects of the Hakka ethnicity exhibited an increased CRC risk (HR = 1.62, 95% CI = 1.09–2.34); however, those who performed regular physical activity exhibited a decreased CRC risk (HR = 0.62, 95% CI = 0.41–0.88). The CRC risk was enhanced in MLH1 germline mutation carriers, with corresponding HRs of 1.72 (95% CI = 1.16–2.55) and 0.54 (95% CI = 0.34–0.83) among subjects of the Hakka ethnicity and those who performed regular physical activity, respectively. In addition, the total cohort with a manual occupation had a 1.56 times higher CRC risk (95% CI = 1.07–2.27) than did that with a skilled occupation. Moreover, MSH2 germline mutation carriers with blood group type B exhibited an increased risk of CRC development (HR = 2.64, 95% CI = 1.06–6.58) compared with those with blood group type O. Furthermore, individuals with TP53 Arg72Pro GC+GG genotypes were associated with increased risk of CRC development (HR = 1.82, 95% CI = 1.19-2.75) compared with those with CC genotype, especially in MLH1 germline mutation carriers (HR = 2.08, 95% CI = 1.31-3.28). Mutation carriers with MLH1 -93A>G GG genotype were associated with an increased risk of CRC development for total cohort (HR = 1.47, 95% CI = 1.10-1.98) and for MLH1 germline mutation carriers (HR = 1.40, 95% CI = 1.04-1.89). However, polymorphism in MSH2 IVS10+12A>G was not associated with risk of CRC. In addition, a significant multiplicative interaction was observed between MSH2 IVS10+12A>G and tea consumption (P=0.014).
Conclusion
The present study revealed that Hakka ethnicity, manual occupation, blood group B, TP53 Arg72Pro Arg allele and MLH1 -93A>G polymorphism were associated with an increased risk of CRC. However, regular physical activity was associated with decreased CRC risk in patients with MLH1 and MSH2 germline mutation.
Keywords: Risk Factors, Genetic Polymorphisms, Colorectal Cancer, Lynch Syndrome, Taiwan |
