| Part Ⅰ:Study on risk prediction of esophageal cancer in Chinese populationGenome-wide association studies (GWAS) have identified multiple genetic variants associated with risk of esophageal squamous-cell carcinoma (ESCC) in Chinese populations. In this study, we examined whether these genetic factors, along with non-genetic factors, could contribute to ESCC risk prediction. We examined25single nucleotide polymorphisms (SNPs) and4non-genetic factors (sex, age, smoking and drinking) associated with ESCC risk in9,805cases and10,493controls from Chinese populations. Weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) were calculated and logistic regression was used to analyze the association between wGRS or GRS and ESCC risk. We calculated the area under the curve (AUC) using receiver-operation-characteristic curve analysis to measure the discrimination after adding genetic variants to the model with only non-genetic factors. Net reclassification improvement (NRI) was used to quantify the degree of correct reclassification using different models. wGRS of the combined17SNPs with significant marginal effect (G SNPs) increased～4-fold ESCC risk (P=1.49×10-164) and the associations were significant in both drinkers and non-drinkers. However, wGRS of the8SNPs with significant effect in gene×drinking interaction (GE SNPs) increased～4-fold ESCC risk only in drinkers (Pinteration=8.76×10-41). The AUC for a risk model with4non-genetic factors,17G SNPs,8GE SNPs and their interactions with drinking was70.9%, with the significant improvement of7.0%compared with the model with only non-genetic factors (P<0.0001). Our results indicate that incorporating genetic variants, life-style factors and their interactions in ESCC risk models can be useful for identifying patients with ESCC. However, additional risk variants including rare risk variants are still need to be discovered by further studies to update this risk prediction model.Part Ⅱ:Data mining of esophageal cancer genome-wide association studyDifferent types of human cancer may share the same genetic susceptibility region. To test this hypothesis, we conducted association studies between variants at chromosome13q22.1, which has previously been identified as a susceptibility locus for pancreatic cancer and various other cancers in digestive system. By using imputation analysis and logistic regression analysis, we found two variants, rs1924966and rs115797771located respectively in the upstream and intronic region of KLF5, associated with risk of ESCC in a case-control cohort comprising6,177cases and6,179controls recruited from Beijing, Hebei province and Hubei province (rs1924966, OR=0.84,95%CI:0.80-0.89, P=1.37×10∷10; rs115797771, OR=0.69,95%CI:0.62-0.78,2.32×10-10). These two SNPs were also proved to be associated with cardiac cancer risk (rs1924966, OR=0.84,95%CI:0.77-0.93, P=0.0003; rs115797771, OR=0.73,95%CI:0.60-0.89, P=0.0018) but not gastric cancer (rs1924966, OR=1.04,95%CI:0.93-1.16, P=0.5001; rs115797771, OR=0.82,95%CI:0.65-1.05, P=0.1123) and colorectal cancer (rs1924966, OR=0.89,95%CI:0.79-1.00, P=0.0527; rs115797771, OR=1.16,95%CI:0.91-1.48, P=0.2265). Additionally, we found that rs11579771is associated with length of survival of patients with stage IV ESCC. Compared with the AA genotype, the AC and CC genotypes had longer survival time (8months vs24months, P=0.0021). Fine-mapping of this genetic region revealed a single base (A/-) Indel variant (rs58090485) that was also associated with risk of ESCC. This Indel variant is located in the promoter region of KLF5and is in strong linkage disequilibrium with rs115797771(r2=0.94). Biochemical assays showed that the A deletion disturbs a transcriptional repressor binding site and results in increased expression of KLF5compared with the A insertion. These results suggest that genetic variants at13q22.1are associated with risk of multiple types of cancer in the digestive system, which might point out an important role of KLF5in the carcinogenesis. |
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