Association Between Genetic Variations In LIN28/let-7 Pathway And Wilms Tumor Susceptibility

Wilms tumor is the most common urologicmalignancy in children and associated with the genetic variation of genes.The resear-ch on screening susceptible individuals and molecular genetic analysis of Wilms tumor will provide theoretical basis for earlv warning and diagnosis.The latest studies have indicated that LIN28/let-7 pathway is involved in the occurrence and development of Wilms tumor,but little is known about its mechanism.The association between genetic variations in LIN28/let-7 pathway and Wilms tumor susceptibility has not been clarified.Objective:To investigate the correlation between genetic variants of key genes in LIN28/let-7 pathway and the risk of Wilms tumor,and to find out the risk genotypes associated with Wilms tumor in Chinese population.Methods:(1)We performed a four-center hospital-based case-control study including 355 Wilms tumor cases and 1070 controls with the purpose to determine whether the potentially functional single nucleotide polymorphisms(SNPs)inLIN28/let-7 pathway core genes are associated with Wilms tumor risk in Chinese children.DNA was extracted and genotyping was performed using TaqMan assays.Genotype frequencies of the polymorphisms and the demographic variables betweenWilms tumor cases and controls were compared using the chi-squaredtest.The associations between the selected polymorphisms and Wilms tumor risk were measured by calculating the odds ratios(ORs)and 95%confidence intervals(CIs),using unconditional univariate and multivariate logistic regression analyses.Stratified analysis was used to identif'y the association between genotypes in subgroups and the risk of Wilms tumor.We also explore the risk haplotypes,so as to find out the SNPs related to Wilms tumor susceptibility.(2)We also conducted the expression quantitative trait loci(eQTL)analysis using GTEx portal web site,to predict the influence of SNPs onexpression level.Paraffin-embedded tissue samples with different genotypes were selected for immunohistochemistry to analyze the effects of different genotypes on protein expression.Results:1.LIN28A rs3811463 T>C and rs34787247 G>A were associated with increased risk of Wilms tumor.Compared to non-carriers,subjects with 1 risk genotype and 1-3 risk genotypes were more likely to develop Wilms tumor.We also found that presence of 1-3 risk genotypes were associated with Wilms tumor risk in subgroups>18 months of age,females,males,and those with clinical stage ?+?diseases.2.LIN28B rs314276 C>A was associated with decreased risk of Wilms tumor.Individuals with 1-4 risk genotypes had a significantly increased risk compared to those with no risk genotypes.Carriers with rs314276 CA/AA genotype had a more protective effect in males>18 months of age and in clinical stage ?+? diseases.Individuals carrying 1-4 risk genotypes have significant risk effects in men under 18 months of age and those with clinical stages ?+? diseases.3.Individuals harboring KRAS rs 12587 GT genotype were more likely to develop Wilms tumor than those carrying the GG genotype.Compared to individuals without a risk genotype,those harboring 1-3 risk genotypes had a significantly increased risk of Wilms tumor.KRAS rs 12587 GT/TT was associated with Wilms tumor risk in children>18 months old.4.No associations with risk of Wilms tumor were found for the selected SNPs of the HMGA2 gene.However,in stratified analysis.carriers with rs968697 TC/CC genotypes presented asignificant risk in males.Individuals with 1-3 protective genotypes were associated with a reduced risk of Wilms tumor in females.5.No associations with risk of Wilms tumor were found for the selected SNPs of the CYMC gene.Conclusion:The LIN28A rs3811463 T>C and rs34787247 G>A,LIN28B rs314276 C>A and KRAS rs 12587 G>T may contribute to risk of Wilms tumor in Chinese population.More centers,larger,prospective studies with different ethnic populations are warranted to validate our findings.