Molecular Epiderniological Study On Genetic Polymorphisms In Long Noncoding RNAs And Colorectal Cancer Risk

Background and ObjectivesColorectal cancer (CRC) is one of the most commonly diagnosed digestive cancer types worldwide. According to IARC, there is an estimation of more than 1.36 million new cases and 0.69 million deaths in 2012. The incidence rates of colorectal cancer are increasing rapidly in China which was historically at low risk because of the changes in lifestyle. Colorectal cancer has became a major public health problem.The etiology of colorectal cancer is considered to be influened by environmental risk factors on a background of consitutional and acquired genetic variations. Modifiable risk factors include dietary factors and lifestyle-related factors such as dietary intake, physical activities, smoking and moderate-to-heavy alcohol drinking. In addition to these environmental factors, genetic variations of colorectal cancer-related genes contribute substantially to the risk as well. Long noncoding RNAs (lncRNAs) are 200nt to 10kb noncoding RNAs that have been recently discovered and intimately linked to cancer. We hypothesized that genetic polymorphisms, such as single nucleotide polymorphisms (SNPs) in lncRNAs may modify the genetic risk of colorectal cancer.Materials and MethodsIn the current application, we propose to explore the associations between SNPs in lncRNAs, environment exposures and colorectal cancer development through two main steps:bioinformatic search and the two-stage colorectal cancer case-control study. In the bioinformatic search part, we plan to construct a genome-wide lncRNA SNP database containing all the SNPs that are located within lncRNAs using the most updated lncRNA databases, and select SNPs that are potentially related CRC on the basis of lncRNA expression profiling databases and SNP function prediction softwares. The study population consists of subjects enrolled in a population-based case-control study conducted in Jiashan County from 1990 to 2014. The study was approved by the Medical Ethical Committee of Zhejiang University School of Medicine. Stage One included 320 cases and 319 controls, Stage Two included 501 cases and 538 controls. Face-to-face interviews were conducted by trained interviewers, who administered a structured questionnaire relating to demographic characteristics and life style factors. After interview,5 ml blood sample was collected into sodium citrate anticoagulant tubes and stored at -80℃ for DNA isolation.102 Single nucleotide polymorphisms were selected and genotyped using the MassARRAY Genotyping System. All statisitical analyses were performed using SAS 9.2, Stata 11.2 and R 2.13.0.ResultsA total of 821 cases and 857 controls with DNA samples available for subsequent analyses were included in the current study. Compared with controls, colorectal cancer cases in our study were currently married, more likely to have a family history of cancer and have the habit of tea drinking. There was no difference in the distribution of gender, age, BMI, occupation, education, smoking and alcohol drinking.The mutation of RP11-650L12.2 rs149941240 was associated with an increased risk of colorectal cancer under the dominant (TTCC/DEL+DEL/DEL vs. TTCC/TTCC: OR=1.406,95% CI:1.143-1.730) or the co-dominant model (TTCC/DEL vs. TTCC/TTCC:OR= 1.471,95% CI:1.185-1.825). The heterozygous variant genotype of rs 10845671 located in the promoter of RP11-392P7.6 was associated with an increased risk of colorectal cancer (CA vs. CC:OR=1.416,95% CI:1.120-1.789). In addition, the genetic variant of rs60226884 and rs 10250402 in RP5-884M6.1 was associated with a increased risk of colorectal cancer. Otherwise, the heterozygous variant genotype of rsl3230517 located in the promoter of RP11-3N2.1 was associated with a decreased risk of colorectal cancer (GA vs. GG:OR=0.739,95% CI:0.594-0.920). Stratified analyses by smoking, alcohol drinking and tea drinking revealed significant gene-environment interactions on colorectal cancer risk.ConclusionsThe current study explored the associations between genetic polymorphisms in lncRNA and risk of colorectal cancer. The findings of our study are as follows:(1) The genomic lncRNA SNPs database included 801173 SNP in 11780 lncRNAs; the colorectal cancer related lncRNA SNPs database included 65805 SNP in 1065 lncRNAs.(2)lncRNA RP11-650L12.2 rs149941240, RP11-392P7.6 rs10845671, RP5-884M6.1 rs60226884 and rs10250402 were associated with an increased risk of colorectal cancer The genetic variant of rs13230517 in RP11-3N2.1 was associated with a decreased risk of colorectal cancer.(3) Significant gene-environment interactions were observed between genetic polymorphisms in lncRNA and smoking, alcohol drinking on colorectal cancer risk.In summary, the findings from our population-based genetic association analysis provide the evidence of a linkage between genetic variations in lncRNA and colorectal carcinogenesis. Confirmation studies with larger sample size and further mechanistic investigations into the function of these biomarkers are warranted to advance our understanding of their roles in colorectal tumorigenesis, and to aid in the development of novel and targeted therapeutic strategies.