Polymorphisms exist in several genes involved in nucleotide excision repair (NER), the principal pathway for removal of smoking-induced DNA damage. An epidemiologic study was conducted to determine whether these polymorphisms modify the association between smoking and breast cancer. DNA samples and exposure histories were analyzed as part of a large population-based case-control study of breast cancer in North Carolina. The study population included 2311 cases (894 African Americans, 1417 whites) and 2022 controls (788 African Americans, 1234 whites). Odds ratios (ORs) were calculated for breast cancer and smoking, and for breast cancer and nine non-synonymous coding polymorphisms in six NER genes (XPD codons 312 and 751, RAD23B codon 249, XPG codon 1104, XPC codon 939, XPF codons 415 and 662, and ERCC6 codons 1213 and 1230). Modification of ORs for smoking by single and combined NER genotypes was investigated. In this study population, smoking was more strongly associated with breast cancer in African American women compared with white women. Among African American women, the association of breast cancer and smoking was strongest among women with specific combinations of NER genotypes. Evidence for multiplicative interaction was found between combined NER genotypes and smoking dose (likelihood ratio test P = 0.06), duration (P = 0.09), time since cessation (P = 0.02), age at initiation (P = 0.04) and former smoking (P = 0.03). No interactions were observed in white women. Therefore, polymorphisms in NER genes may modify the relationship between breast cancer and smoking. These results are consistent with previous evidence of exposure-specific p53 mutations in breast tumors from current and former smokers, suggesting that smoking may play a role in breast cancer etiology.
The HER2 codon 655 polymorphism may be one of many low-penetrant genes that make a minor contribution to breast cancer, particularly in subgroups of women. Additional large studies, as well as data pooling, will be needed to estimate the contribution of such genes to breast cancer risk.
Purpose Evaluating genetic susceptibility may clarify effects of known environmental factors and also identify individuals at high risk. We evaluated the association of four insulin-related pathway gene polymorphisms in insulin-like growth factor-1 (IGF-I) (CA)n repeat, insulin-like growth factor-2 (IGF-II) (rs680), insulin-like growth factor binding protein-3 (IGFBP-3) (rs2854744), and adiponectin (APM1 rs1501299) with colon cancer risk, as well as relationships with circulating IGF-I, IGF-II, IGFBP-3, and C-peptide in a population-based study. Methods Participants were African Americans (231cases, 306 controls) and Whites (297 cases, 530 controls). Consenting subjects provided blood specimens, and lifestyle/diet information. Genotyping for all genes except IGF-I was performed by the 5′-exonuclease (Taqman) assay. The IGF-I (CA)n repeat was assayed by PCR, and fragment analysis. Circulating proteins were measured by enzyme immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Results The IGF-I (CA)19 repeat was higher in White controls (50%) than African American controls (31%). Whites homozygous for the IGF-I (CA)19 repeat had a nearly two fold increase in risk of colon cancer (OR=1.77; 95%CI=1.15–2.73), but not African Americans (OR= 0.73, 95%CI 0.50–1.51). We observed an inverse association between the IGF-II Apa1 A-variant and colon cancer risk (OR= 0.49, 95%CI 0.28–0.88) in Whites only. Carrying the IGFBP-3 variant alleles was associated with lower IGFBP-3 protein levels, a difference most pronounced in Whites (p- trend < 0.05). Conclusions These results support an association between insulin pathway-related genes and elevated colon cancer risk in Whites but not in African Americans.
IntroductionNonsteroidal anti-inflammatory drugs (NSAID) have been associated with reduced risks of colon cancer, breast cancer, and other cancer sites (1, 2). We previously reported a strong inverse relationship between NSAID use and breast cancer in a North Carolina study, with a suggestion of stronger associations among African Americans (3). One hypothesized mechanism for the reduction in cancer risk by NSAIDs is the inhibition of cyclooxygenase 2 (COX2), which is overexpressed in various cancer types and is thought to stimulate angiogenesis and inhibit apoptosis (1).A polymorphism in the COX2 gene [valine to alanine at residue 511 (Val 511 Ala)] has been identified in African Americans that results in a conformation change in the enzyme near its active site, and it has been hypothesized this polymorphism could modify biochemical function or change the response to NSAIDs (4, 5). In a recent paper, carriers of this polymorphism seemed to be at reduced risk for colon adenomas [odds ratio (OR), 0.56; 95% confidence interval (95% CI), 0.25-1.27] and colon cancer (OR, 0.67; 95% CI, ref. 5). In this report, we describe the relationship between the COX2 Val 511 Ala polymorphism, NSAIDs, and breast cancer in a case-control study in North Carolina. Materials and MethodsThese analyses were based on 1,441 African American participants in the Carolina Breast Cancer Study, a population-based, case-control study conducted between 1993 to 2001 (3, 6). Cases were 20 to 74 years old and had either invasive breast cancer or carcinoma in situ. Control women were selected from Division of Motor Vehicle and Health Care Financing Administration lists and matched by race and age to cases.Genotyping was done according to previously described procedures using the Taqman system (6). The Ala 511 (C) allelespecific probe was labeled on the 5Vend with the VIC reporter dye and contained the nucleotide sequence 5V-TGCTCCAgCTTCTAC-3Vwith a melting temperature of 68.5jC and a G-C content of 53.3%. The Val 511 (T) allele-specific probe was labeled on the 5V end with the 6-FAM reporter dye and contained the nucleotide sequence 5V-TGCTCCAaCTTCTAC3Vwith a melting temperature of 67.5jC and a G-C content of 46.7%. Both probes were minor groove binding and used a nonfluorescing quencher on the 3V end. Forward and reverse primers were used to amplify the region surrounding the Val 511 Ala polymorphism. The nucleotide sequences for the forward and reverse primers were 5V-AGAAAAGCCTCGGC-CAGATG-3V and 5V-GGCAGGAGAACATATAACATTACC-CATAA-3V, respectively.Logistic regression analyses were done using the GENMOD procedure in SAS (Cary, NC). We calculated ORs and 95% CIs to evaluate the association between breast cancer and the Val 511 Ala polymorphism and the joint effects of NSAIDs and genotype. ResultsGenotyping results were available for 763 cases (673 invasive and 90 in situ) and 678 controls. The frequency of the Ala allele was 4.3% in cases and 4.0% in controls (Table 1), which is very similar to the allele frequency of 4.5% reported by Lin et al. (5)...
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