Polymorphisms in Methionine Synthase, Methionine Synthase Reductase and Serine Hydroxymethyltransferase, Folate and Alcohol Intake, and Colon Cancer Risk

Background/Aims - We examined associations among folate and alcohol intake, SNPs in genes involved in one-carbon metabolism and colon cancer risk. Methods - Colon cancer cases (294 African Americans and 349 whites) were frequency matched to population controls (437 African Americans and 611 whites) by age, race and sex from 33 North Carolina counties from 1996 to 2000. Folate and alcohol intakes were collected by dietary interview. Five SNPs were genotyped using DNA from whole blood: SHMT C1420T; MTRR A66G; MTR A2756G, and the previously-reported MTHFR C677T and MTHFR A1298C. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. Results - An inverse association was observed for SHMT TT genotype as compared to CC genotype in whites (OR=0.6, 95%CI=0.4, 1.0), but not in African Americans. Inverse associations were observed for high folate intake in individuals carrying 0 or 1 variant allele [OR 0.2 (95%CI 0.06-0.8) for African Americans; OR 0.2 (95%CI 0.1-0.6) for whites] compared to low folate intake. Modest interactions between these SNPs and alcohol or folate intakes were observed. Conclusions - Our results are consistent with other findings and provide needed data on these associations among African Americans

5,10-Methylenetetrahydrofolate Reductase 677 and 1298 Polymorphisms, Folate Intake, and Microsatellite Instability in Colon Cancer

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a critical role in folate metabolism. Studies on the association between MTHFR polymorphisms and length changes in short tandem repeat DNA sequences [microsatellite instability (MSI)] are inconsistent. Using data from colon cancer cases (n = 503) enrolled as part of an existing population-based case-control study, we investigated the association between MTHFR 677 and MTHFR 1298 polymorphisms and MSI. We also examined whether the association was modified by folate intake. Participants were case subjects enrolled as part of the North Carolina Colon Cancer Study. Consenting cases provided information about lifestyle and diet during in-home interviews as well as blood specimens and permission to obtain tumor blocks. DNA from normal and tumor tissue sections was used to determine microsatellite status (MSI). Tumors were classified as MSI if two or more microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250) had changes in the number of DNA sequence repeats compared with matched nontumor tissue. Tumors with one positive marker (MSI-low) or no positive markers (microsatellite stable) were grouped together as non-MSI tumors (microsatellite stable). MTHFR 677 and MTHFR 1298 genotypes were determined by real-time PCR using the 5′ exonuclease (Taqman) assay. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (95% CI). MSI was more common in proximal tumors (OR, 3.8; 95% CI, 1.7–8.4) and in current smokers (OR, 4.0; 95% CI, 1.6–9.7). Compared with MTHFR 677 CC referent, MTHFR 677 CT/TT genotype was inversely associated with MSI among White cases (OR, 0.36; 95% CI, 0.16–0.81) but not significant among African Americans. Although not statistically significant, a similar inverse association was observed between MTHFR 677 CT/TT genotype and MSI among the entire case subjects (OR, 0.54; 95% CI, 0.26–1.10). Among those with adequate folate intake (>400 μg total folate), we found strong inverse associations between combined MTHFR genotypes and MSI (677 CC + 1298 AC/CC, OR, 0.09; 95% CI, 0.01–0.59; 677 CT/TT + 1298 AA, OR, 0.13; 95% CI, 0.02–0.85) compared with the combined wild-type genotypes (677 CC + 1298 AA). This protective effect was not evident among those with low folate (<400 μg total folate) intake. Our results suggest that MTHFR variant genotypes are associated with reduced risk of MSI tumors under conditions of adequate folate intake, although the data are imprecise due to small numbers. These results indicate that the relationship between MTHFR genotypes and MSI is influenced by folate status

UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans

Glucuronidation by the UDP-glucuronosyltransferase enzymes (UGTs) is one of the primary detoxification pathways of dietary heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). In a population-based case-control study of 537 cases and 866 controls, we investigated whether colon cancer was associated with genetic variations in UGT1A1 and UGT1A9 genes and we determined if those variations modify the association between colon cancer and dietary HCA and PAH exposure. We measured functional UGT1A1 polymorphisms at positions −53 (*28; A(TA)6TAA to A(TA)7TAA), −3156 (G>A), −3279 (T>G) and the UGT1A9-275(T>A) polymorphism, and found no association with colon cancer overall. However, when stratified by race, the UGT1A1-3279 GG/TG intermediate/low activity genotypes were associated with an increased risk of colon cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI)=1.1–2.0) in Caucasians. This finding is also supported by haplotype analyses where the UGT1A1-3279G-allele-bearing haplotype is overrepresented in case group. Overall, UGT1A1-53 and -3156 genotypes modified the association between dietary benzo(a)pyrene (BaP) and colon cancer (P for interaction=0.02 and 0.03, respectively). The strongest association was observed for those with <7.7 ng/day BaP exposure and the low activity genotypes, for both UGT1A1*28/*28 (OR=1.8, 95% CI=1.1–2.9) and −3156AA (OR=1.7, 95% CI=1.0–3.0), compared to ≥7.7 ng/day and combined high/intermediate genotypes. These data support a hypothesis that UGTs modify the association between meat-derived PAH exposure and colon cancer by their role in the elimination of dietary carcinogens

Polymorphisms in Methionine Synthase, Methionine Synthase Reductase and Serine Hydroxymethyltransferase, Folate and Alcohol Intake, and Colon Cancer Risk

We examined associations among folate and alcohol intake, SNPs in genes involved in one-carbon metabolism and colon cancer risk

Smoking and Selected DNA Repair Gene Polymorphisms in Controls: Systematic Review and Meta-Analysis

When the case-only study design is used to estimate statistical interaction between genetic (G) and environmental (E) exposures, G and E must be independent in the underlying population, or the case-only estimate of interaction (COR) will be biased. Few studies have examined the occurrence of G-E association in published control group data

Modification by N-acetyltransferase 1 genotype on the association between dietary heterocyclic amines and colon cancer in a multiethnic study

Colorectal cancer incidence is greater among African Americans, compared to whites in the U.S., and may be due in part to differences in diet, genetic variation at metabolic loci, and/or the joint effect of diet and genetic susceptibility. We examined whether our previously reported associations between meat-derived heterocyclic amine (HCA) intake and colon cancer were modified by N-acetyltransferase 1 (NAT1) or 2 (NAT2) genotypes and whether there were differences by race

Breast Cancer Subtypes and Previously Established Genetic Risk Factors: A Bayesian Approach

Gene expression analyses indicate that breast cancer is a heterogeneous disease with at least 5 immunohistologic subtypes. Despite growing evidence that these subtypes are etiologically and prognostically distinct, few studies have investigated whether they have divergent genetic risk factors. To help fill in this gap in our understanding, we examined associations between breast cancer subtypes and previously established susceptibility loci among white and African-American women in the Carolina Breast Cancer Study

Replication of Breast Cancer Susceptibility Loci in Whites and African Americans Using a Bayesian Approach

Genome-wide association studies (GWAS) and candidate gene analyses have led to the discovery of several dozen genetic polymorphisms associated with breast cancer susceptibility, many of which are considered well-established risk factors for the disease. Despite attempts to replicate these same variant-disease associations in African Americans, the evaluable populations are often too small to produce precise or consistent results. We estimated the associations between 83 previously identified single nucleotide polymorphisms (SNPs) and breast cancer among Carolina Breast Cancer Study (1993–2001) participants using maximum likelihood, Bayesian, and hierarchical methods. The selected SNPs were previous GWAS hits (n = 22), near-hits (n = 19), otherwise well-established risk loci (n = 5), or located in the same genes as selected variants (n = 37). We successfully replicated 18 GWAS-identified SNPs in whites (n = 2,352) and 10 in African Americans (n = 1,447). SNPs in the fibroblast growth factor receptor 2 gene (FGFR2) and the TOC high mobility group box family member 3 gene (TOX3) were strongly associated with breast cancer in both races. SNPs in the mitochondrial ribosomal protein S30 gene (MRPS30), mitogen-activated protein kinase kinase kinase 1 gene (MAP3K1), zinc finger, MIZ-type containing 1 gene (ZMIZ1), and H19, imprinted maternally expressed transcript gene (H19) were associated with breast cancer in whites, and SNPs in the estrogen receptor 1 gene (ESR1) and H19 gene were associated with breast cancer in African Americans. We provide precise and well-informed race-stratified odds ratios for key breast cancer–related SNPs. Our results demonstrate the utility of Bayesian methods in genetic epidemiology and provide support for their application in small, etiologically driven investigations

Intrinsic Breast Tumor Subtypes, Race, and Long-Term Survival in the Carolina Breast Cancer Study

Previous research identified differences in breast cancer-specific mortality across four "intrinsic" tumor subtypes: luminal A, luminal B, basal-like, and human epidermal growth factor receptor 2 positive/estrogen receptor negative (HER2+/ER−)