Genetic Variations In MYCL1 Are Associated With Small-Cell Lung Cancer Susceptibility And Prognosis

Background and Objective:microRNAs (miRNAs) have been shown to play significant roles in diverse cellular processes including proliferation, differentiation and apoptosis. which are all involved in tumor development and progression. Single nucleotide polymorphisms (SNPs) located at 3'untranslated regions (UTR) of genes might modulate the expression of genes by affecting their binding ability to certain miRNAs, therefore, be associated with individual susceptibility to cancer development or prognosis. This study sought to identify genetic variations within 3'UTR of genes that are shown to be dysregulated in small-cell lung cancers and evaluated their effects on susceptibility to and prognosis of the cancer.Methods:NextBio search engine (www.nextbio.com) was used to find genes dysregulated in RNA level in small-cell lung cancer and the existed database.Patrocles (www.patrocles.org) was used to identify putative SNPs within miRNA target sites. The associations between the identified SNP and susceptibility to small-cell lung cancer were examined in a case-control set consisted of 666 patients with small-cell lung cancer and 758 controls derived from a Han Chinese population. Genotypes were determined by polymerase chain reaction-based restriction fragment length polymorphism and odds ratios (ORs) and their 95% confidence intervals (95% CIs) were computed with unconditional logistic regression models. The associations of genotypes with overall survival of small-cell lung cancer were investigated in a subset of 239 patients treated with the same platinum-based chemotherapy by Cox proportional model. A set of biochemical assays was performed to examine the function of SNPs.Results:We identified two SNPs, rs3134615 G>T and rs2291854 C>T, located respectively in the 3'UTR of the MYCL1 and ASCL1 genes, which were suggested to be miRNA binding sites by bioinformatics analysis. Case-control analysis showed that the rs3134615T allele was associated with significantly increased risk for small-cell lung cancer, with the OR for carrying at least one T allele (GT or TT genotype) being 1.87 (95% CI=1.26-2.77; P=0.002) compared with the GG genotype. In addition, a supermultiplicative joint effect between rs3134615 and smoking was observed, with the OR for carrying the variant genotypes and heavy smoking being 3.92 (95% CI 2.08-7.39). Although the association between rs2291854 and the risk of small-cell lung cancer was not significant (OR=1.26,95% CI=0.96-1.64), it was significant in males (OR=1.40,95% CI=1.03-1.91). Analysis of overall survival in 239 patients received the same chemotherapy revealed that rs3134613 but not rs3134615 was associated with small-cell lung cancer survival. It was shown that the rs3134613GG or GT genotype had longer overall survival time compared with the TT genotype [22 months (95% CI 19-25) or 19 months (95% CI=16-22) versus 16 months (95% CI=11-21), P=0.002 and P=0.047, respectively]. Cox proportional model analyses showed that the adjusted hazard ratios of death for the GT and GG genotypes were 0.61 (95% CI=0.42-0.90, P= 0.012) and 0.44 (95% CI=0.29-0.69, P<0.001), respectively, compared with the TT genotype, indicating rs3134613 SNP as an independent prognostic factor. Luciferase reporter gene assays suggested that the MYCL1 transcript is a target of hsa-miR-1827 and hsa-miR-1827 exhibited stronger inhibition of the rs3134615G-containing MYCL1 transcript compared with the rs3134615T-containing MYCL1 transcript.Conclusions:These results suggest that the SNPs in MYCL1 gene may be associated with the development and prognosis of small-cell lung cancer, which might be mediated by altered regulation of MYCL1 expression in the posttranscription level by hsa-miR-1827.