MicroRNA Polymorphisms And Risk Of Head And Neck Squamous Cell Carcinoma In A Chinese Population

Head and neck cancer (HNC), mainly head and neck squamous cell carcinoma (HNSCC), represents the sixth most common cancer worldwide. In recent years, with the continuous improvement of treatment, the cure rate of head and neck cancer has improved, but the prognosis is still poor. HNSCC is one of main causes contributing to disease related to deaths and a serious one to be resolved in public health. Smoking and drinking mainly contribute to the development of HNSCC, but only a small fraction of smokers develop this disease, suggesting that there is an inter-individual variation in genetic susceptibility to HNSCC under the small exposure. Single nucleotide polymorphism (SNP) is the main form of genetic variation among individuals. Therefore, it is of great significance to search for SNPs associated with head and neck cancer, and to use it in the screening of patients with head and neck cancer, and have a profound significance in early diagnosis and early treatment of head and neck cancer.Micro-RNAs (miRNAs) are 20-24 nt single-stranded RNA molecules that could repress the expression of specific target genes by binding to the 3’untranslated regions (UTRs) of messenger RNAs (mRNAs). MiRNAs have been investigated to make significant contributions to the maintenance of different biological processes, such as cell proliferation, differentiation and apoptosis. A single miRNA may regulate the expression of many genes, and it has been proposed that more than one third of all protein-coding genes are under translational control by miRNAs. Numerous studies have demonstrated that aberrant expression of miRNAs is closely associated with proliferation, invasion, metastasis and the prognosis of various cancers including HNSCC. The study of miRNAs related to genetic variations has great clinical significance.At present, the most widely studied miRNAs mainly included miR-149, miR-146a, miR-605, and miR-196a2 miR-608. A number of literatures have reported that the above miRNAs were closely related to many kinds of tumors including HNSCC, but the results are not consistent. In addition, a recent study found that miR-101 polymorphisms were associated with the pathogenesis of tumor. Thus, we performed a study on SNPs in above miRNAs and HNSCC risk in Chinese Han population. This may help to find out biomarkers for HNSCC susceptibility for Chinese Han population and provide important clues to individual prevention, intervention and treatment.Part I:Associations between Polymorphisms in key miRNAs and HNSCC risk in a Chinese populationBased on previous reports about miRNA polymorphisms and cancer risk, we choose five most investigated and potentially functional SNPs (ie. rs2292832 in miR-149, rs2910164 in miR-146a, rs2043556 in miR-605, rs4919510 in miR-608 and rs11614913 in miR-196a2) for genotyping using Illumina Infinium Human Exome BeadChip in 576 HNSCC patients historically confirmed by two pathologists and 1552 cancer-free controls frequency matched to the cases on age (±5 years) and sex. In this case-control study, we evaluated the associations between the five selected SNPs and HNSCC risk and investigated the effects of environmental factors on HNSCC susceptibility in Chinese Han.The results revealed that rs2043556 in miR-605(dominant model:adjusted OR = 0.78,95% CI= 0.64-0.95; additive model:adjusted OR= 0.80,95% CI= 0.68-0.94) and rs11614913 in miR-196a2 (dominant model:adjusted OR= 1.24,95% CI= 1.00-1.54; additive model:adjusted OR= 1.19,95% CI= 1.04-1.37) were significantly associated with risk of HNSCC, respectively. Furthermore, when these two loci were evaluated together by the number of putative risk alleles (rs2043556 A and rs11614913 G), a significant locus-dosage effect was found between the groups and risk of HNSCC (Ptrend=0.001). However, no significant association was detected between other three SNPs (rs2292832, rs2910164 and rs4919510) and HNSCC risk.Our study provided the evidence that rs2043556 and rs11614913 may have an impact on genetic susceptibility to HNSCC in Chinese population.Part Ⅱ:Associations between Polymorphisms in miR-101 and HNSCC risk in a Chinese populationThe region including both 10 kb upstream and downstream of miR-101-1 and miR-101-2 genes were targeted and 11 functional SNPs (rs75365、rs1011210、 rs555146、rs578481、rs705509、rs462480、rs17718377、rs4742051、rs1537146、 rs10974820、rs1053872) were selected. Genotyping was performed using Illumina Infinium Human Exome BeadChip in 576 HNSCC patients historically confirmed by two pathologists and 1552 cancer-free controls frequency matched to the cases on age (±5 years) and sex. Logistic analysis was conducted to evaluate the associations between the 11 selected SNPs and HNSCC risk. For the main effect analysis, none of the 11 selected SNPs was associated with HNSCC risk. However, in the stratification analysis by tumor sites, rs578481 and rs705509 in pri-miR-101-1 were significantly associated with risk of oral squamous cell carcinoma (OSCC) (rs578481:adjusted OR= 1.19,95% CI:1.01-1.39, P= 0.036; rs705509:adjusted OR= 0.85,95% CI:0.73-0.98, P= 0.030). Furthermore, combined analysis of the two SNPs revealed that subjects carrying the risk alleles of rs578481 and rs705509 had increased risk of OSCC in a dose-response manner (P trend= 0.022).In conclusion, our findings suggested that the SNPs rs578481 and rs705509 locating in pri-miR-101-1 may play a role in genetic susceptibility to OSCC, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis.