| Colorectal cancer(CRC) has become the third largest cancer in men and second in women in world. With the development of aging society, the incidence and mortality of CRC in the elderly population increased year by year. Numerous factors influence the occurrence of CRC. A large number of studies show that circulating insulin-like growth factor-1(IGF-1) is one of the important factors that influence the occurrence and development of CRC.In recent years, more and more studies show that IGF-1 gene polymorphism is closely related to circulating IGF-1 level and the incidence of CRC. This study focused on the level of circulating IGF-1 and the correlation between IGF-1 gene promoter polymorphisms and the risk of CRC among the elderly population in Tianjin.Objectives 1.To explore the risk factors of CRC and the correlation with circulating IGF-1 in the elderly population. 2.To explore the distribution of IGF-1 gene promoter polymorphism in the elderly population. 3.To explore the correlation between IGF-1 gene promoter polymorphism and the risk of CRC as well as circulating IGF-1 level in the elderly population.Contents and Methods 1.During March 2012 to December 2014, 209 patients with colorectal cancer as case group and 208 non-cancer patients as control group were included in Tianjin Union Medicine Center for case-control study. The basic clinical data of all subjects were collected. The serum level of glucose(GLU), triglyceride(TG), total cholesterol(TC), low density lipoprotein(LDL), very low density lipoprotein(VLDL), Leukocyte(WBC) and IGF-1 were determined. The risk factors that may affect the occurrence of CRC were evaluated. The correlation between circulating IGF-1 and clinicopathological Parameters in CRC and the relevance of circulating IGF-1 and basic clinical characteristics were analysed. 2.DNA was isolated from blood of 209 patients with CRC and 208 controls. IGF-1 gene promoter evolutionary conserved regions(ECR)(CA)n repeat and three single nucleotide polymorphisms(SNPs) were assayed by PCR and fragment analysis. The distribution of IGF-1 gene polymorphism in CRC group was analysed. 3. The part of the study on the basis of the previous two further analyzed IGF-1 gene promoter region polymorphism conserved evolutionary correlation with CRC risk and circulating IGF-1 levels.Results 1.The proportion of smoking, alcohol, hypertension, coronary heart disease history in CRC group was significantly higher than that of the control group(P<0.05). The blood glucose, white blood cell and circulating IGF-1 level in CRC group were significantly higher than that of the control group, while triglycerides was lower(P<0.05). According to analysis of covariance, gender, smoking, hypertension, coronary heart disease history, blood glucose higher than 6.10mmol/L, white blood cell higher than 9.5*109/L and IGF-1 higher than 194.31ng/ml were risk factors of CRC. The odds ratio(OR) of patients with higher circulating IGF-1 was 2.77-fold of the lower(95%CI:1.02~7.49). Circulating IGF-1 was significantly higher in patients with CRC with the tumor no less than 5 cm or with advanced stages(stages Ill and IV)or with low differentiation or with regional lymphoid node metastasis than in those with the tumor less than 5 cm or with early stages(stages I and II) or with middle and high differentiation or without regional lymphoid node metastasis. Circulating IGF-1 in the male group was higher than that in the female group and which was decreased with the increasing of age in CRC group. Smokers, drinkers have higher level of IGF-1 than non-smokers and non-drinkers. The higher blood glucose, the higher circulating IGF-1. 2.Among both cases and controls, the genotyped polymorphisms were distributed in compliance to Hardy-Weinberg equilibrium(P>0.05). we observed that the number of IGF-1(CA)n polymorphic repeats for cases and controls ranged from n=11(fragment size 227 bp) to n=26 repeats(fragment size 257 bp). Overall, the most common repeat was n=19(fragment size 243 bp), present in 37.32% of cases and 35.34% of controls.Among them,there were five common alleles(CA) 17,(CA) 18,(CA) 19,(CA) 20,(CA) 21, which accounted for the proportion of more than 95% of all the subjects. Based on repeated CA nucleotides, total 31 genotypes were formed by the above 13 alleles.There were eight common genotypes with a frequency of >5% in our study population: 17/19、18/18、18/19、18/20、18/21、19/19、19/20、19/21.Homozygote 19/19 was the most common genotype both in cases( 20.10%) and controls(15.87%). Among both cases and controls, the most common homozygous genotypes of three SNPs(rs35767、rs5742612、rs2288377) were CC、TT、TT. C-T-T was common in haplotypes consisting of three SNPs, and C-19-T-T was common after(CA) nincluded.The distribution of IGF-1 gene polymorphisms between the two groups showed no significant difference. 3.Male subjects carrying(CA)17 repeat allele were found to be correlated with a reduced risk of CRC as compared with the(CA) 19 allele(OR =0.46, 95%CI: 0.21~0.98). As homozygote(CA)19/(CA)19 was designated the reference, subjects carrying(CA)17/(CA)19 genotype were found to be correlated with a lower risk of CRC(OR=0.36, 95%CI: 0.13~0.99). This association only appeared in men(OR =0.22, 95%CI: 0.05~0.91). Further distinguish cancer sites, subjects carry(CA) 17 /(CA) 19 genotype were found to be correlated with a decreased risk of rectal cancer(OR =0.24, 95%CI: 0.06~0.91), and(CA)18/(CA)20 genotype were found to be correlated with an elevated risk of colon cancer(OR =5.10, 95%CI: 1.15~22.64). Male subjects carrying TT genotype and CT/TT genotypes of rs35767 were found to be correlated with an elevated risk of CRC(OR =1.91, 95%CI: 1.11~3.26; OR =1.83, 95%CI :1.09~3.06). Moreover,we found that male carriers of TT and CT/TT genotype of rs35767 had a significant higher IGF-1 level as compared with male subjects carrying with CC genotype(P<0.05). Male carriers of CC genotype of rs5742612 had a significant lower IGF-1 level as compared with male subjects carrying with CC genotype(P<0.05).However we didn’t found the the correlation between rs5742612 and the risk of CRC.After unit three SNPs we found that subjects carrying T-T-T haplotype had a significant higher IGF-1 level as compared with subjects carrying C-T-T haplotype(P<0.05). After unit three SNPs and(CA)n, we we didn’t found the the correlation with the risk of CRC and circulating IGF-1 level.Conclusions 1. Smoking, hypertension, coronary heart disease, high blood glucose, white blood cell, and circulating IGF-1 level were risk factors in the elderly population with CRC. Circulating IGF-1 was closely related to the clinicopathological parameters in colorectal cancer. Stay away from cigarettes, low-sugar fat diet may reduce the risk of CRC to some extent. 2.The distribution of IGF-1 gene promoter polymorphism in the elderly patients with CRC was not difference. 3. IGF-1 gene promoter polymorphisms were correlation with the risk of CRC and circulating IGF-1 level. The aged population carrying with(CA)17/(CA)19 genotypes were found to be correlated with a decreased risk of rectal cancer.(CA)18/(CA)20genotypes were associated with increased risk of colon cancer. 4.The aged men carrying with CT/TT genotypes in rs35767 were associated with increased risk of CRC by adjusting circulating IGF-1 level. Male carriers of CC genotype of rs5742612 had lower IGF-1 level, while subjects carrying C-T-T haplotype had higher IGF-1 level. However, it was not found to be associated with CRC risk. |
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