The association between IGF1 CA repeat polymorphisms and breast cancer risk: a meta-analysis

IGF-I CA repeat polymorphisms have been reported to influence the risk for breast cancer in many studies; however, the results still remains controversial and ambiguous. Therefore, to determine more precise estimations for the relationship, a meta-analysis was performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the association. A total of 9 studies including 5641 cases and 10471 controls were involved in this meta-analysis. All studies investigated the association between (CA)19 repeat polymorphism and breast cancer risk. Of those, four studies investigated the association between (CA)20 repeat polymorphism and breast cancer risk (2585 cases and 2847 controls), and three studies were for (CA)17 repeat polymorphism (2122 cases and 2225 controls). The overall odds ratio (OR) for the (CA)19 versus non-(CA)19 allele was 1.002 (95% CI 0.972–1.033). There was no suggestion of an overall effect either in recessive or dominant modeling of (CA)19 allele effects (dominant model: OR = 1.000 95% CI 0.872–1.147; recessive model: OR = 0.959 95% CI 0.888–1.036). The comparison of (CA)19 homozygosity versus non-(CA)19 homozygosity also showed no differential susceptibility to breast cancer (OR = 0.974, 95% CI 0.838–1.132). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found among premenopausal or postmenopausal women. When stratified by ethnicity, no significant association was found in all genetic models. Furthermore, there was no evidence that two other alleles associated with the risk of breast cancer (CA17 vs. non-CA17: OR = 1.165 95% CI 0.634–2.141; CA20 vs. non-CA20: OR = 1.019 95% CI 0.909–1.143). In conclusion, the current meta-analysis suggests that three IGF-I (CA) repeat polymorphisms had no association to breast cancer risk.     

Haplotype-based association studies of IGFBP1 and IGFBP3 with prostate and breast cancer risk: the multiethnic cohort.

Collective evidence suggests that the insulin-like growth factor (IGF) system plays a role in prostate and breast cancer risk. IGF-binding proteins (IGFBP) are the principal regulatory molecules that modulate IGF-I bioavailability in the circulation and tissues. To examine whether inherited differences in the IGFBP1 and IGFBP3 genes influence prostate and breast cancer susceptibility, we conducted two large population-based association studies of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Whites. To thoroughly assess the genetic variation across the two loci, we (a) sequenced the IGFBP1 and IGFBP3 exons in 95 aggressive prostate and 95 advanced breast cancer cases to ensure that we had identified all common missense variants and (b) characterized the linkage disequilibrium patterns and common haplotypes by genotyping 36 single nucleotide polymorphisms (SNP) spanning 71 kb across the loci ( approximately 20 kb upstream and approximately 40 kb downstream, respectively) in a panel of 349 control subjects of the five racial/ethnic groups. No new missense SNPs were found. We identified three regions of strong linkage disequilibrium and selected a subset of 23 tagging SNPs that could accurately predict both the common IGFBP1 and IGFBP3 haplotypes and the remaining 13 SNPs. We tested the association between IGFBP1 and IGFBP3 genotypes and haplotypes for their associations with prostate and breast cancer risk in two large case-control studies nested within the Multiethnic Cohort [prostate cases/controls = 2,320/2,290; breast cases (largely postmenopausal)/controls = 1,615/1,962]. We observed no strong associations between IGFBP1 and IGFBP3 genotypes or haplotypes with either prostate or breast cancer risk. Our results suggest that common genetic variation in the IGFBP1 and IGFBP3 genes do not substantially influence prostate and breast cancer susceptibility.     

Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk

Purpose

Insulin-like growth factor 1 (IGF1) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis. The bioavailability of IGF1 is regulated by the insulin-like growth factor binding protein 3 (IGFBP3). The purpose of this study was to examine the association of genetic variants in IGF1 (rs6214, rs6220, and rs35767) and IGFBP3 (rs2854744 and rs2854746) with risk of colorectal polyps and colorectal cancer.

Methods

In this ongoing colorectal cancer study of Austria (CORSA), a total of 3,360 Caucasian participants, consisting of 178 colorectal cancer patients, 328 patients with high risk polyps, 1,059 patients with low risk colorectal polyps, and 1,795 colonoscopy-negative controls, were recruited within a large colorectal screening project in the province Burgenland and from three hospitals in Vienna. Multiple logistic regression was applied to compare individuals of the control group against three different risk groups, namely, colorectal cancer group, high risk polyp group, and low risk polyp group.

Results

Carriers of the homozygous polymorphic genotype of the SNP rs6214 were associated with an increased colorectal risk (OR = 1.79, 95% CI 1.04–1.90) compared to the colonoscopy-negative controls; this was also found when combining colorectal cancer cases and high risk polyp group (OR = 1.39, 95% CI 1.01–1.90).

Conclusion

Our results suggest that the SNP rs6214 of IGF1 could have an impact on developing colorectal cancer and colorectal polyps with villous elements.     

A nested case-control study of stomach cancer and serum insulin-like growth factor (IGF)-1, IGF-2 and IGF-binding protein (IGFBP)-3

We conducted this study to investigate the association between serum levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF-binding protein (IGFBP)-3 and the incidence of stomach cancer. A nested case-control study of 161 stomach cancer incidences and 314 matched controls was established within the Japan Collaborative Cohort Study. The adjusted ORs for IGF-1 quartile ranged from 0.84 and 1.13, but these were not statistically significant. Further, higher IGF-2 levels did not significantly correlate with the incidence of stomach cancer. A tendency for the risk of stomach cancer to decrease with increasing IGFBP-3 level was observed, but without statistical significance. A slight decrease in risk was seen with an increase in IGFBP-3 level, but neither change was statistically significant. To conclude, we found no association between IGF-1, IGF-2, or IGFBP-3 serum levels and the risk of stomach cancer. As this association has not been established, these findings need to be confirmed in future studies.     

Meat consumption among Black and White men and risk of prostate cancer in the Cancer Prevention Study II Nutrition Cohort.

Previous epidemiologic studies have suggested that intake of red meat may be associated with increased risk of prostate cancer. Few studies, however, have examined these associations by race. We examined intake of red meat, processed meat, and poultry in relation to incident prostate cancer among Black and White men in the Cancer Prevention Study II Nutrition Cohort. Participants in the study completed a detailed questionnaire on diet, medical history, and lifestyle in 1992 to 1993. After excluding men with a history of cancer and incomplete dietary information, 692 Black and 64,856 White men were included in the cohort. During follow-up through August 31, 2001, we documented 85 and 5,028 cases of incident prostate cancer among Black and White men, respectively. Cox proportional hazards models were used to estimate rate ratios (RR) and 95% confidence intervals (95% CI). No measure of meat consumption was associated with risk of prostate cancer among White men. Among Black men, total red meat intake (processed plus unprocessed red meat) was associated with higher risk of prostate cancer (RR, 2.0; 95% CI, 1.0-4.2 for highest versus lowest quartile; P(trend) = 0.05); this increase in risk was mainly due to risk associated with consumption of cooked processed meats (sausages, bacon, and hot dogs; RR, 2.7; 95% CI, 1.3-5.3 for highest versus lowest quartile; P(trend) = 0.008). This study suggests that high consumption of cooked processed meats may contribute to prostate cancer risk among Black men in the United States.     

IGF1 CA repeat polymorphisms, lifestyle factors and breast cancer risk in the Long Island Breast Cancer Study Project

Insulin-like growth factor I (IGF-I) is an important regulator of growth and differentiation and is a potent mitogen for human breast cancer cells. Recent investigations suggest an association between cytosine-adenine dinucleotide (CA)n repeat polymorphisms of the IGF1 gene and IGF-I levels and further evidence indicates that genotype may influence breast cancer risk. We assessed the relation between IGF1 (CA)n repeats and breast cancer, and evaluated modification of genotype effects according to traditional breast cancer risk factors in 1028 breast cancer cases and 1086 controls. An increased risk of breast cancer was seen for genotypes that included alleles with fewer than (CA)19 repeats when compared to (CA)19 repeat carriers, an association that was particularly strong among premenopausal women [odds ratio (OR)=3.31; 95% confidence interval (CI)=1.47, 7.48]. No significant association was observed between an IGF1 genotype with no (CA)19 repeat compared to (CA)19 repeat genotypes in either pre- or postmenopausal women overall. However, when traditional breast cancer risk factors were considered, premenopausal women with genotypes that lacked a (CA)19 repeat had a nearly 60% increased risk of breast cancer among those who had ever used hormonal birth control, while never users had a significantly reduced risk (Pinteraction=0.01). Among postmenopausal women, those with genotypes lacking a (CA)19 repeat allele had significantly increased breast cancer risk among subjects with a lower than median body mass index (BMI) (OR=1.77 95% CI=1.09, 2.87), while no association for IGF1 genotype was seen among women with a higher than median BMI (Pinteraction=0.04). Our results demonstrate a role for alleles with fewer than (CA)19 repeats as a risk factor for breast cancer and also suggest that several traditional breast cancer risk factors modify the association of the IGF1 (CA)19 repeat genotype.     

2型糖尿病合并胃癌患者血清IGF-1、IGFBP-3的变化

目的:研究2型糖尿病（diabetes mellitus,DM）合并胃癌（gastric cancer,GC）患者血清胰岛素样生长因子-1（insulin-like growth factor-1,IGF-1）、胰岛素样生长因子结合蛋白-3(insulin-like growth factor binding protein-3,IGFBP-3)的变化。方法:选择2型DM患者30例（DM组）、2型DM合并GC患者48例（DM并GC组）为研究对象,ELISA 法测定血清IGF-1、 IGFBP-3水平;同时测定空腹血糖、空腹胰岛素、血脂水平。 结果:DM并GC组的IGF-1、IGF-1/IGFBP-3比值高于DM组（P<0.05）,IGFBP-3在两组之间无统计学差异（P>0.05）。IGF-1、IGF-1/IGFBP-3比值与空腹胰岛素水平呈正相关（r=0.598,0.626,P=0.000）,IGF-1/IGFBP-3比值是DM并GC患者淋巴结转移的危险因素（OR=2.142,P=0.001）。结论:IGF-1可能参与2型DM合并GC的发生及淋巴结转移。     

Vitamin D receptor genotypes/haplotypes and prostate cancer risk.

The vitamin D receptor (VDR) gene has been associated with prostate cancer, although previous results are somewhat equivocal. To further study this, we did a family-based case-control study (N = 918) of the association between prostate cancer and six common VDR variants: Cdx2, FokI, BsmI, ApaI, TaqI, and the poly-A microsatellite. Looking at each variant alone, only FokI and ApaI were associated with disease. The FokI FF genotype was inversely associated with prostate cancer among men with less advanced disease (i.e., Gleason score <7 and tumor stage 相似文献   

Insulin-like growth factor-binding protein-3 gene -202 A/C polymorphism is correlated with advanced disease status in prostate cancer

The circulating level of insulin-like growth factor-binding protein-3 (IGFBP-3) is inversely associated with the risk of prostate cancer (PCa) and its progression and may be modulated by the A/C polymorphism at position -202 in the promoter region of IGFBP-3. This study was conducted to evaluate the role of the A/C polymorphism as a genetic modifier in the etiology of PCa and its disease status. The polymorphism was analyzed by a PCR restriction fragment-length polymorphism technique in 307 PCa patients, 221 benign prostatic hyperplasia (BPH) patients, and 227 male controls. No significant difference in the genotype frequency was found between the PCa or BPH patients and controls (PCa versus control, P = 0.316; BPH versus control, P = 0.964). Regarding the tumor stage, the C allele was more frequently observed in patients having tumors with higher stage (P for trend = 0.002). When the PCa patients with localized disease (stage A + B + C) were considered as reference, those with CC and AC genotype had a significantly increased risk of metastatic disease (stage D) compared with those with AA genotype [age-adjusted odds ratio (aOR) = 3.89, 95% confidence interval (CI) = 1.42-10.64, P = 0.008, and aOR = 1.68, 95% CI = 1.01-2.79, P = 0.044, respectively]. The presence of the C allele appeared to be associated with an increased risk of metastatic PCa with a gene dosage effect (aOR = 1.82, 95% CI = 1.23-2.68, P = 0.002). Similarly, significant findings were also observed when PCa patients were compared between those with organ-confined disease (stage A + B) and those with extra-prostatic extension (stage C + D). Furthermore, the C allele was present more frequently in patients with higher tumor grade. In conclusion, the IGFBP-3 -202 A/C polymorphism was not associated with susceptibility to PCa and BPH in Japanese men, but the presence of the C allele may cumulatively increase the risk for tumor metastasis and for having tumors with a biologically more aggressive phenotype. Because of the significant differences in incidence of clinically evident PCa according to racial backgrounds, the conjecture should be further examined in different racial populations.     

IGF-1 CA repeat variant and breast cancer risk in postmenopausal women

IGF-I is an important growth factor for the mammary gland. We evaluated the relationship of the IGF-I CA(n) polymorphism with breast cancer risk in Caucasian postmenopausal women and performed a meta-analysis of published data. The IGF-I CA(n) polymorphism was genotyped in 4091 from the Rotterdam Study. A disease-free survival analysis was performed along with a meta-analysis of all available data on IGF-I CA(n) polymorphism and breast cancer risk. During follow-up 159 women were diagnosed with breast cancer. The disease-free survival analysis adjusted for age at entry, age at menopause, body mass index and waist hip ratio yielded a HR=0.97 (95% CI=0.59-1.58) for CA(19) non-carriers against carriers. The meta-analysis using the random-effects model gave a pooled OR of 1.26 (95% CI=0.95-1.82) for IGF-I CA(19) non-carriers versus CA(19) homozygous carriers. According to these results, the IGF-I CA(19) promoter polymorphism is not likely to predict the risk of breast cancer.     

IGF1R和IGFBP3在肺鳞癌中的表达及其临床意义

目的:检测IGF1R、IGFBP3在肺鳞癌组织中的表达,并探讨其在肺鳞癌发生发展中的作用及其临床意义。方法:用免疫组化二步法检测246例肺鳞癌术后组织与40例癌旁正常组织中IGF1R、IGFBP3的表达情况,并分析二者的相关性及与临床病理特征和预后的关系。结果:IGF1R在肺鳞癌组织中的阳性表达明显高于癌旁正常组织,其表达率分别为54.07%、32.5%,IGFBP3在肺鳞癌组织中的阳性表达明显低于癌旁正常组织,其表达率分别为61.79%、87.5%,差异具有统计学意义（P＜0.05）。IGF1R的表达与淋巴结转移正相关（P＜0.05）,IGFBP3的表达与肺癌的TNM分期、淋巴结转移负相关（P＜0.01）,而与其他临床病理参数无关（P＞0.05）。IGF1R阳性表达组患者生存期明显短于IGF1R阴性表达组患者,IGFBP3阳性表达组患者生存期明显长于IGFBP3阴性表达组患者,差异有统计学意义（P分别为<0.001和=0.001）。Cox单因素分析显示TNM分期、淋巴结转移、IGF1R及IGFBP3的表达均与预后相关,将TNM分期、淋巴结转移、IGF1R及IGFBP3的表达进行Cox回归多因素分析,结果显示TNM分期、IGF1R及IGFBP3的表达均为肺鳞癌患者的独立预后因子。IGF1R、IGFBP3在肺鳞癌组织中表达呈负相关（r=-0.204,P＜0.001）。结论:IGF1R、IGFBP3参与了肺鳞癌的发生、发展,并且二者均为肺鳞癌的独立预后因子。有望成为分子靶向治疗的新靶点。     

Prostate cancer risk and ESR1 TA, ESR2 CA repeat polymorphisms.

BACKGROUND: Experimental evidence has suggested that estrogen receptor alpha (coded by the gene ESR1) might increase prostate cancer risk, whereas estrogen receptor beta (coded by the gene ESR2) might reduce prostate cancer risk. METHODS: We investigated the relationship with prostate cancer risk of both a TA repeat polymorphism in the ESR1 5' region, ESR1 (TA)(n), and with a CA repeat polymorphism in intron 5 of ESR2, ESR2 (CA)(n), in a case-control study (545 cases and 674 controls) nested in the Physicians' Health Study. RESULTS: Prostate cancer risk was highest for carriers of ESR1 (TA)(24) and ESR1 (TA)(25). Replacing one modal ESR1 (TA)(14) allele with one ESR1 (TA)(24) allele yielded an odds ratio of 1.42 (95% confidence interval, 1.00-2.00; P=0.05). Replacing one ESR1 (TA)(14) allele with one ESR1 (TA)(25) allele yielded an odds ratio of 2.10 (95% confidence interval, 1.15-3.84; P=0.02). ESR2 (CA)(n) showed no effects on prostate cancer risk. CONCLUSIONS: The ESR1 (TA)(n) polymorphism might play a role in prostate cancer risk.     

CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer.

Previous case-only studies have shown that men with the CYP3A4*1B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A4*1B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (*1/*3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A4*1B and CYP3A5*1 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A4*1B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02-3.57; P=0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01-0.49; P=0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26-1.00; P=0.05). The CYP3A5*1 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22-0.78; P=0.006). As expected based on these genotype-level results, the CYP3A4*1B/CYP3A5*3 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36-6.23; P=0.006), and the CYP3A4*1B/CYP3A5*1 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01-0.51; P=0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness.     

Promoter -202 A/C polymorphism of insulin-like growth factor binding protein-3 gene and non-small cell lung cancer risk

Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Therefore, we attempted to ascertain whether the A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC). Our study included 209 NSCLC patients and 209 age-, gender- and smoking status-matched control subjects. The frequencies of each polymorphic variation in the control population were as follows: AA = 95 (45.5%), AC = 91 (43.5%) and CC = 23 (11.0%). In the NSCLC subjects, the genotypic frequencies were as follows: AA = 131 (62.7%), AC = 73 (34.9%) and CC = 5 (2.4%). We detected statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p < 0.05, Pearson's chi-square test). The NSCLC risk correlated significantly with AA genotype. Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 2.45 (95% CI = 1.17-5.40) and that for the ones with AA genotype was 4.58 (95% CI = 2.17-10.30). These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.     

Polymorphic CAG/CAA repeat length in the AIB1/SRC-3 gene and prostate cancer risk: a population-based case-control study.

In an earlier report, we showed that a shorter CAG repeat length in the androgen receptor (AR) gene is associated with an increased risk of prostate cancer in China, the population with the lowest reported prostate cancer incidence in the world. Because AR coactivators enhance transactivation of AR, in this report we evaluated the relationship of a CAG/CAA repeat length polymorphism in the AIB1/SRC-3 gene (amplified in breast cancer gene 1, a steroid receptor coactivator and an AR coactivator) with prostate cancer risk in a population-based case-control study in China. Genomic DNA from 189 prostate cancer patients and 301 healthy controls was used for the PCR-based assay. The AIB1/SRC-3 CAG/CAA repeat length ranged from 24 to 32, with the most common repeat length being 29. Homozygous 29/29 and heterozygous 28/29 were the most common genotypes, with 44 and 30% of the controls harboring these genotypes, respectively. Relative to subjects homozygous for 29 CAG/CAA repeats (29/29 genotype), individuals with the <29/29 genotype had a nonsignificant 31% increased risk [odds ratio (OR), 1.31; 95% confidence interval (CI), 0.87-1.97], whereas those homozygous for the <29 allele had a significant 81% excess risk (OR, 1.81; 95% CI, 1.00-3.28). The combined effect of CAG repeat lengths in the AR and AIB1/SRC-3 genes was also evaluated. Relative to men with both the 29/29 genotype of the AIB1/SRC-3 gene and a long CAG repeat length (> or =23) in the AR gene, those with both the <29/<29 AIB1/SRC-3 genotype and a short CAG repeat length in the AR gene (<23) had a 2.8-fold risk (OR, 2.78; 95% CI, 1.24-6.26). Together, our data indicate that the CAG/CAA repeat length in the AIB1/SRC-3 gene may be associated with prostate cancer risk in Chinese men and that the combination of CAG/CAA repeat lengths in both the AIB1/SRC-3 and AR genes may provide a useful marker for clinically significant prostate cancer. Expanded studies in other populations are needed to confirm this association and the combined effect of AIB1/SRC-3 and other hormone-related genes in prostate cancer etiology.     

VDR and SRD5A2 polymorphisms combine to increase risk for prostate cancer in both non-Hispanic White and Hispanic White men.

PURPOSE: Vitamin D and dihydrotestosterone pathways interact to promote the growth of prostatic tissue. The nuclear vitamin D receptor (VDR) moderates the actions of vitamin D. 5alpha-Reductase type II (SRD5A2) codes for the enzyme that converts testosterone to dihydrotestosterone in the prostate. This study tested the interactions of VDR (CDX2, FokI) and SRD5A2 (V89L, A49T) polymorphisms, and their associations with prostate cancer. EXPERIMENTAL DESIGN: This genetic association study included 932 non-Hispanic White (NHW) men and 414 Hispanic White (HW) men from South Texas. Cases had biopsy-confirmed cancer; controls had normal digital rectal exams and serum prostate-specific antigen levels of <2.5 ng/mL. RESULTS: Using logistic regression analyses to test associations with prostate cancer, only the V89L polymorphism (VV genotype compared with LL/LV) in HW men was statistically significant [odds ratios (OR), 0.64; 95% confidence intervals (95% CI), 0.41-0.99]. The interaction terms for FokI and V89L in NHW men and CDX2 and V89L in HW men in the logistic model were significant (P = 0.02 and 0.03, respectively). When stratified by V89L genotype, the FokI polymorphism (TT/TC versus CC) was significantly associated with prostate cancer in NHW men with the V89L VV genotype (FokI OR, 1.53; 95% CI, 1.06-2.23). The CDX2 polymorphism (GG versus AG/AA) was significantly associated with prostate cancer only in HW men with the V89L VV genotype (CDX2 OR, 3.16; 95% CI, 1.39-7.19; interaction term P = 0.02). CONCLUSION: Our results indicate that the SRD5A2 V89L VV genotype interacts with VDR FokI TT/CT genotypes in NHW men and VDR CDX2 GG genotypes in HW men to increase the risk for prostate cancer.