Background: Vitamin D is hypothesized to lower the risk of breast cancer by inhibiting cell proliferation via the nuclear vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNP) in the VDR gene (VDR), rs1544410 (BsmI), and rs2228570 (FokI), have been inconsistently associated with breast cancer risk. Increased risk has been reported for the FokI ff genotype, which encodes a less transcriptionally active isoform of VDR, and reduced risk has been reported for the BsmI BB genotype, a SNP in strong linkage disequilibrium with a 3′-untranslated region, which may influence VDR mRNA stability. Methods: We pooled data from 6 prospective studies in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium to examine associations between these SNPs and breast cancer among >6,300 cases and 8,100 controls for each SNP using conditional logistic regression. Results: The odds ratio (OR) for the rs2228570 (FokI) ff versus FF genotype in the overall population was statistically significantly elevated [OR, 1.16; 95% confidence interval (95% CI), 1.04-1.28] but was weaker once data from the cohort with previously published positive findings were removed (OR, 1.10; 95% CI, 0.98-1.24). No association was noted between rs1544410 (BsmI) BB and breast cancer risk overall (OR, 0.98; 95% CI, 0.89-1.09), but the BB genotype was associated with a significantly lower risk of advanced breast cancer (OR, 0.74; 95% CI, 0.60-0.92). Conclusions: Although the evidence for independent contributions of these variants to breast cancer susceptibility remains equivocal, future large studies should integrate genetic variation in VDR with biomarkers of vitamin D status. (Cancer Epidemiol Biomarkers Prev 2009;18(1):297–305)

Much uncertainty remains about the type of sunlight exposure that most increases risk of cutaneous melanoma and the role of diet. The authors conducted a population-based case-control study (1986–1992) of Caucasians living on Oahu, Hawaii; included were 278 cases and age- and sex-matched controls. Plasma samples were measured for retinol, carotenoids, and alpha-tocopherol by high-pressure liquid chromatography. Selenium was measured in blood and toenails by neutron activation. Celtic and English ancestries, migration to Hawaii before age 20 years, fair complexion, inability to tan, and family history of skin cancer, as well as height, hours spent in the summer sun, blistering sunburns during adolescence, and moles, all increased melanoma risk. With regard to diet and biomarkers, only alcohol was associated with risk. The odds ratios for increasing tertiles of lifetime ethanol intake were 1.0, 1.2 (95% confidence interval (CI): 0.6, 2.2), and 2.3 (95% CI: 1.2, 4.4) (p for trend = 0.01) for men and 1.0, 1.1 (95% CI: 0.5, 2.4), and 1.7 (95% CI: 0.7, 3.8) (p for trend = 0.19) for women. Dietary lipids were unrelated to risk, but polyunsaturated fat intake appeared to modify the effects of alcohol and toenail selenium on melanoma risk. These data provide additional evidence for the association of constitutional susceptibility factors, intense sun exposure (particularly before age 20 years), and alcohol consumption with melanoma risk.

Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P-trend = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P-trend = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.

In the normal intestinal epithelium transforming growth factor β-1 (TGFβ-1) acts as a growth inhibitor, but in malignant cells it may act as a tumor promoter. However, only limited information is available on genetic variation in the TGFB1 gene and its relationship to circulating levels and risk of colorectal cancer. To characterize associations of genetic variation [tagging single-nucleotide polymorphisms (tagSNP) and haplotypes with frequency >0.05] at the TGFB1 locus with circulating TGFβ-1 and risk of colorectal neoplasia, we conducted two case-control studies (including 271 colorectal adenoma cases and 544 controls, and 535 colorectal adenocarcinoma cases and 656 controls) among Japanese Americans, Caucasians, and Native Hawaiians in Hawaii. Serum TGFβ-1 was measured by sandwich ELISA among the subjects of the first study. The variant A allele for tagSNP rs6957 was associated with higher serum TGFβ-1 [means (in ng/mL) and 95% confidence interval (95% CI) for AA or AG, 32.6 (30.6–34.7); GG, 29.0 (25.1–32.9); P_difference = 0.05] after adjusting for age and other factors. Homozygous carriers of the variant G allele for tagSNP rs11466345 had a statistically significantly lower risk of adenocarcinoma [AG versus AA: odds ratio (OR), 0.9 (95% CI, 0.7–1.2); GG versus AA: OR, 0.4 (95% CI, 0.2–0.7); P_trend = 0.01]. The haplotype carrying both variants was also statistically significantly associated with a reduced risk of adenocarcinoma (OR, 0.3; 95% CI, 0.1–0.8). Although not statistically significant, the direction and magnitude of the corresponding ORs were similar for adenoma. These results suggest that a haplotype containing SNP rs11466345 at the 3′ end of TGFB1 is associated with genetic susceptibility to colorectal neoplasia. [Cancer Res 2008;68(4):1236–44]