| Gastric cancer is one of the most common cancers of the world, which threatens the human’s life and health seriously. China now bears the greatest burden from gastric cancer of the world. Identifying the influence factors of gastric cancer development may greatly promot the development of strategies and methods for gastric cancer prevention and has a significance in public health. The tumorigenesis of gastric cancer is a complex process with multiple steps, and influenced by both environmental and genetic factors. Helicobacter Pylori infection, N-nitroso compounds and polycyclic aromatic hydrocarbons explosion, salted food consumption, tobacoo use and alchol drinking have been demonstrated as the major risk factors in gastric cancer developmemt. In addition, the difference of inheritable background may also lead to different gastric cancer susceptibility. Cancer is disease with highly complexity and extensive heterogeneity. Although several gastric cancer related factors have been found, more effort on mechanism researching is needed to find out the underlying cause of gastric cancer.Telomeres, consisting of tandem repeats of TTAGGG nucleotides, cap the ends of eukaryotic chromosomes. Telomeres are crucial in maintaining chromosomal stability and integrity through prohibiting abnormal events, such as nuclease degradation, chromosome ends fusion, and aberrant recombination. During somatic cell divisions, telomeres progressively shorten, and reflect the senescence of cells to some extent. Therefore, telomere length was regard as a potential biomarker that can indicate the risk of age-related disease such as cancer. Although the telomere length of tissue derived cells can providing more direct evidence than peripheral blood leucocyte cells for the relationship between telomere length and cancer risk. Telomere length of peripheral blood leucocyte cells is now being widely analyzed in association studies between telomere length and cancer risk, with its high accessibility and little trauma.Furthermore, telomere length are strongly correlated between different tissues, although the telomere length is diverse in differenet tissues.Epidemiology studies have found that, peripheral blood leucocyte cells telomere length is highly associated with several factors, such as aging, sex, smoking, poor nutrition, aerobic physical exercise, chronic inflammation and psychological health status. In addition, telomere length has been proved being associated with a wide variety of diseases risk. Several studies reported that telomere length was associated with multiple cancer risk, but the results were inconsistent. Helicobacter Pylori infection is an established cause of gastric cancer. Recent study found that Helicobacter Pylori infection may also induced telomeres shorten. These evidences suggest that telomere length maybe an indicater of gastric cancer. However, two recent case-control studies, which reported significant associations between telomere length and gastric cancer risk, only with relative small sample size. Therefore, further studies based enough samples are warranted to clearly illustrate the correlation between telomere length and gastric cancer risk.Telomere length not only affected by environmental factors, but also influenced by genetic factors. It is estimated that the heritability of telomere length varying between 44% and 80%. Recent genome-wide association studies(GWAS) have identified several genetic variants were associated with telomere length in populations of European descent, including genes involved in the formation and activity of telomerase such as TERC and TERT. Currently, evidence for the relationship between genetic variants and telomere length in Chinese population is insufficient and whether the telomere length related genetic variants can modify the gastric cancer risk is not clear.Therefore, we firstly conducted a case-control study with a relative large sample size to investigate the relationship between telomere length and gastric cancer risk. Furthermore, we conducted a genome-wide association study to explore the relationship between telomere length and genetic variants and futher evaluate the effect of telomere length related genetic variants on gastric cancer susceptibiligy.Part I: A case-control study on the association between telomere length and gastric cancer riskGenome instability which is induced by telomere dysregulation is a hallmark of cancer. The significant associations between telomere length and common cancer risk have been widely reported in several epidemiology studies. However, only few studies were involved in gastric cancer. Furthermore, the sample size of these studies were small and results were inconsistent. Liu et al conducted a study in 396 gastric cancer cases and 378 controls of Han Chinese and reported a significant association between short telomeres and increased gastric cancer risk(odds ratio [OR] = 2.14, 95% confidence interval [95%CI]: 1.52-2.93). However, another prospective cohort study in European population has not found a significant association between telomere length and gastric cancer risk 1.04(95%CI: 0.77-1.39).Therefore, we conducted a case-control study with large sample size to investigate the relationship between telomere length and gastric cancer risk. We use quantitative PCR method to measure the telomere length. In brief, relative telomere length(RTL) were determined by the ratio of telomere repeat copy number(T) to single copy gene copy number(S) and expressed as T/S ratio. 1,136 gastric cancer cases were recruited from hospitals in Jiangsu province. 1,012 cancer-free controls were randomly selected from a community-based screening program for non-infectious diseases, and were frequency-matched to cases based on age and sex. Logistic regression was used to analyze the gastric cancer risk of subjects in different telomere length group, and compute the OR and 95%CI. The restricted cubic spline curve was used to analyze the potential dose-response relationship between telomere length and gastric cancer risk. All samples were run in duplicate and the mean of two measurements was used in the statistical analyses. Technicians were blinded to the case-control status.As a result, telomere length was significantly associated with age and sex. Telomere in elders(Median: 1.39, IQR: 1.08-1.68) was shorter than that in youngers(1.58, 1.32-1.93, P<0.001). Women(1.58, 1.24-1.94) showed significantly longer telomeres than men(1.46, 1.17-1.75, P<0.001) among controls. The telomere length in cases(1.28, 0.94-1.69) was shorter than that in controls(1.49, 1.20-1.80, P<0.001). Restricted cubic spine function in the logistic regression model revealed an obvious U-shaped association for gastric cancer risk(P <0.001). As compared with the lowest risk subjects in the fourth quintile, a significant dose-response effect was observed between increased risk of gastric cancer and decreasing telomeres of the third, second and first quintiles, with ORs(95%CIs) ranging from 1.28(0.93-1.77), 1.65(1.21-2.26) to 3.81(2.82-5.13), furthermore an increased risk of gastric cancer was also observed in the fifth quintile 1.78(1.30-2.44).In summary, this study revealed an “U” shape relationship between telomere length and gastric cancer risk and demonstrates that subjects with either short or extreme long telomeres may have an increased risk of gastric cancer. This study provided valuable clues for better understanding the underlying mechanism of gastric carcinogenesis.Part II: Genome-wide association study for telomere lengthIn recent years, genome-wide association study(GWAS) have been widely used in association studies between telomere length and genetic variants, and have identified genetic variants on chromosome 2p16.2(ACYP2), 3q26(TERC), 5p15.33(TERT), 4q32.2(NAF1), 10q24.33(OBFC1), 19p12(ZNF208) and 20q13.3(RTEL1) that were associated with telomere length in populations of European descent. Thess studies provided valuable clues for elustrating the genetic mechanism of telomere in Europeans. However, there was little evidence for telomere length related genetic variants in Chinese population. Although Liu et al conducted a telomere length GWAS study in Chinese population and reported two promising telomere length related loci(5p13.33, rs2736100, P=1.93×10-5; 12q13.13, rs17653722, P=6.96×10-6). But these two loci have not reached genome-wide significance(P<5×10-8).Therefore, we performed a telomere length GWAS analysis in two Chinese cohorts based on Affymetrix Gene Chip Human Mapping 6.0 and Illumina Omni Zhonghua Genotyping Chip. The GWAS I comprised 1,012 individuals from Changzhou community-based screening program for non-infectious diseases and GWAS II comprised 948 individuals from Zhangjiagang community-based physical examination. We conducted meta-analysis of these two GWAS data using inverse variance weighting. The promising signals in GWAS discovery stage were further replicated in 867 subjects from Shandong using Sequenom Mass ARRAY genotying platform. We further analyzed the relationship between eight genetic variants that were reported by recent European telomere length GWAS and telomere length in Changzhou cohort. We also evaluated effects of these eight variants on gastric cancer susceptibiligy bases cases and controls subjects from Part I. Generalized linear models were used to conduct tests for correlation between RTL and genetic variants. Logistic regression was used to estimate the OR and 95%CI for gastric cancer risk in each genetic variant, RTL or WGS.As a result, rs78744096 located in 9p24.1 was significantly associated in all three populations(GWAS I: β=0.470,P=1.79×10-3; GWAS II: β=0.509,P=8.04×10-4;replication: β=0.0.145, P=0.038;combined: β=0.248, P=2.31×10-6). We evaluated the correlation between genetic variants and telomere length among 1,012 controls based on both the genotypes of single variant and the WGS of all eight variants. In the single variant analysis, we found that rs2736100 on chromosome 5p15.33(TERT) exhibited a nominally significant association with RTL after adjusted for age and sex(P=0.012). In the WGS analysis, we did observe significant correlation between WGS and RTL in controls(P <0.001), which was more solid than any of the variants alone. We did not found significant association between telomere length related variants and gastric cancer risk.In this study, we identified 9p24.1 may affect telomere length for the first time and replicated the correlation between telomere length related variants in Europeans and telomere length in Chinese population. However, we did not found variant that can affect gastric cancer susceptibility. This study sysmatically evaluated the relationship between telomere length, genetic variants and gastric cancer risk. Our not only provided valuable clues for better understanding the genetic regulating mechanism of telomere length, but also, our methodology and data resources may as an important reference for further studies. |
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