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Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs3802842 is not the functional single-nucleotide polymorphism (SNP), but is in linkage disequilibrium (LD) with a functional SNP(s). We performed ChIP-seq for histone modifications in SW480 and HCT-116 CRC cells, and incorporated ChIP-seq and DNase I hypersensitivity data available through ENCODE within a 137-kb genomic region containing rs3802842 on 11q23.1. We identified SNP rs10891246 in LD with rs3802842 that mapped within a bidirectional promoter region of genes C11orf92 and C11orf93. Following mutagenesis to the risk allele, the promoter demonstrated lower levels of reporter gene expression. A second SNP rs7130173 was identified in LD with rs3802842 that mapped to a candidate enhancer region, which showed strong unidirectional activity in both HCT-116 and SW480 CRC cells. The risk allele of rs7130173 demonstrated reduced enhancer activity compared with the common allele, and reduced nuclear protein binding affinity in electromobility shift assays compared with the common allele suggesting differential transcription factor (TF) binding. SNPs rs10891246 and rs7130173 are on the same haplotype, and expression quantitative trait loci (eQTL) analyses of neighboring genes implicate C11orf53, C11orf92 and C11orf93 as candidate target genes. These data imply that rs10891246 and rs7130173 are functional SNPs mapping to 11q23.1 and that C11orf53, C11orf92 and C11orf93 represent novel candidate target genes involved in CRC etiology.

Obesity is a known risk factor for colon cancer and higher body mass index (BMI) has been associated with colorectal adenomas, which are precursor lesions to most colorectal cancers. Polymorphisms in the fat-mass and obesity-associated (FTO) gene have been associated with BMI and larger effects in older versus younger children have been reported. However, no studies have examined associations between FTO polymorphisms, BMI throughout adulthood and colorectal adenomas. Therefore, we evaluated associations between FTO polymorphisms (rs1421085, rs17817449, rs8050136, rs9939609, rs8044769), adult BMI (at recruitment, 50s, 40s, 30s, 20s age decades) and colorectal adenomas in 759 Caucasians and 469 African-Americans. We found that the highest versus the lowest BMI tertile at recruitment [odds ratio (OR) = 1.82; 95% confidence interval (CI): 1.07-2.16] and in the 30s (OR = 1.50; 95% CI: 1.04-2.15) was associated with higher adenoma risk. Stratification by ethnicity revealed that these associations only remained significant in Caucasians. We found that, in Caucasians, having two versus no copies of the variant allele in rs17817449, rs8050136 and rs9939609, which are all in strong linkage disequilibrium, was associated with higher BMI in the 30s and 40s but none of the polymorphisms were associated with adenomas. In African-Americans, having one or two copies of the variant in rs17817449 (OR = 0.61; 95% CI: 0.39-0.95) and rs8050136 (OR = 0.59; 95% CI: 0.38-0.93) was associated with colorectal adenomas and, having two variant copies in rs17817449 and rs8050136 was associated with higher BMI at recruitment and in the 40s, respectively. Our results are consistent with prior studies and show for the first time that FTO polymorphisms are associated with colorectal adenomas in African-Americans.

Two recent genome-wide association studies (GWAS) identified three common variants in SMAD7 (rs4464148, rs4939827 and rs12953717) that confer modest susceptibility to colorectal cancer. Here, we replicated the association of rs4464148 with colon cancer in a population-based case-control study (561 cases and 721 controls). Compared with the TT genotype, those with CT and CC had an adjusted odds ratio (OR) and 95% confidence interval of 1.06 (0.82-1.38) and 1.86 (1.17-2.96), respectively (P(trend) = 0.04). However, stratified analyses revealed that this association was limited to women only [OR = 1.25 (0.88-1.78) for CT and OR = 2.76 (1.53-4.98) for CC, P(trend) = 0.002, P(interaction) = 0.08], which was not noted in any GWAS. Similarly, we found evidence for association with both rs4939827 and rs12953717 in women only (P = 0.007 in dominant rs4939827 model and P = 0.015 in recessive rs12953717 model), but not in men (P > 0.05) and evidence of an interaction with gender (P = 0.015 for rs4939827 and P = 0.061 for rs12953717). Similar effect modification was found in haplotype analyses. Our data add evidence supporting these genetic variants as markers predisposing to colon cancer, specifically in women.

Previous studies have examined the role of higher trans-fatty acid consumption on prostate cancer risk, but the results remain unclear. Any potential association may be modified by variants in genes involved with immune and inflammatory responses. To investigate this, we undertook a case-control study (N = 1012) of the association between trans-fatty acid intake and advanced prostate cancer, and evaluated whether this effect was modified by a functional polymorphism in the RNASEL gene (R462Q). Among Caucasians (N = 834), we observed that each type of trans-fatty acid and total trans-fatty acid intake showed a statistically significant positive association with prostate cancer, but only weakly increased risk for the isomers of cis-fatty acids. Compared with the lowest quartile of total trans-fatty acid consumption, the higher quartiles gave odds ratios (ORs) equal to 1.58 [95% confidence interval (CI): 1.00, 2.48], 1.95 (95% CI: 1.20, 3.19) and 2.77 (95% CI: 1.60, 4.79) (P-trend = 0.0003); this effect was modified by the RNASEL R462Q polymorphism (P(interaction) = 0.01). Among men with the QQ/RQ genotype, the association between total trans-fatty acid intake and prostate cancer was substantially stronger [ORs of higher quartiles equal to 2.93 (95% CI: 1.62, 5.30), 3.13 (95% CI: 1.64, 5.98) and 4.80 (95% CI: 2.29, 10.08), respectively]. For men with the RR genotype, total trans-fatty acid intake was not associated with disease. This suggests that among Caucasians, positive association between higher trans-fatty acid consumption and prostate cancer may be modified by the functional RNASEL variant R462Q.

To date, the potential impact of hormones on prostate cancer has predominantly focused on receptor-mediated events. However, catechol estrogens, if not inactivated by catechol-O-methyltransferase (COMT), can generate large quantities of reactive oxygen species (ROS). ROS may cause a spectrum of damage including oxidative DNA base lesions, which can lead to irreversible mutation(s) if they are not repaired by base excision repair (BER) systems. hOGG1 is a key enzyme in short patch BER because it recognizes and performs initial excision of the most common form of oxidative DNA base damage, 8-hydroxyguanine (8-oxo-dG). To investigate potential non-receptor-mediated estrogen effects, we evaluated the association between COMT Val158Met and hOGG1 Ser326Cys polymorphisms and prostate cancer in a family-based case-control study (439 prostate cancer cases, 479 brother controls). We observed no noteworthy associations between these polymorphisms and prostate cancer risk in the total study population. However, among men with more aggressive prostate cancer, the hOGG1 326 Cys/Cys genotype was inversely associated with disease (OR=0.30; 95% CI=0.09-0.98). Combining the lower activity CYP1B1 432 Leu/Leu or Leu/Val genotypes (which may decrease the level of catechol estrogens and ROS generated) with the hOGG1 326 Cys/Cys genotype and the XRCC1 399 Arg/Arg or Arg/Gln genotypes (which may enhance BER) resulted in an even further reduced risk in Caucasians with more aggressive disease (OR=0.09; 95% CI=0.01-0.56). Including the high-activity COMT 158Val allele to this combination also lowered aggressive prostate cancer risk but the effect was not as strong (OR=0.20; 95% CI=0.05-0.88). The decreased risk we observed with the hOGG1 326 Cys/Cys genotype confirms an earlier report and the further reduced risk found with the CYP1B1 (432 Leu/Leu or Leu/Val)-hOGG1 (326 Cys/Cys)-XRCC1 (Arg/Arg or Arg/Gln) genotype combination may lend new insights to the importance of ROS generated from non-receptor-mediated estrogenic mechanisms in more aggressive prostate cancer.

We previously reported linkage of a prostate cancer tumor aggressiveness locus to chromosome 7q32-q33, a region also associated with a high frequency of allelic imbalance in prostate tumors. The smallest region of allelic imbalance contains the podocalyxin-like (PODXL) gene, which we evaluate here as a candidate prostate cancer aggressiveness gene mapping to 7q32-q33. DNA from probands of linked families was examined for germ-line mutations in PODXL. A variable in-frame deletion, four missense variants and two nonsense variants were identified in linked men. Variants that affected amino acid sequence were further evaluated for association with risk of prostate cancer and tumor aggressiveness in a family-based case-control population (439 cases and 479 sibling controls). The presence of any single in-frame deletion was positively associated with prostate cancer [odds ratio (OR)=2.14, 95% confidence interval (95%CI)=1.09-4.20, P=0.03] and the presence of two copies of any deletion further increased risk (OR=2.58, 95%CI=1.23-5.45, P=0.01). This finding was strengthened when stratifying among men with more aggressive disease (high grade or stage): OR=3.04 for one deletion (95%CI=1.01-9.15) and OR=4.42 for two deletions (95%CI=1.32-14.85, P=0.02). A weak positive association was also observed between prostate cancer risk and PODXL variant 340A (in linkage disequilibrium with another variant, 587T) (OR=1.48, 95%CI=1.02-2.14, P=0.04). These results implicate PODXL as a candidate prostate cancer tumor aggressiveness gene mapping to chromosome 7q32-q33.

The objective of this study was to provide more accurate frequency estimates of breast cancer susceptibility gene 1 ( BRCA1 ) germline alterations in the ovarian cancer population. To achieve this, we determined the prevalence of BRCA1 alterations in a population-based series of consecutive ovarian cancer cases. This is the first population-based ovarian cancer study reporting BRCA1 alterations derived from a comprehensive screen of the entire coding region. One hundred and seven ovarian cancer cases were analyzed for BRCA1 alterations using the RNase mismatch cleavage assay followed by direct sequencing. Two truncating mutations, 962del4 and 3600del11, were identified. Both patients had a family history of breast or ovarian cancer. Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer. The frequency distribution of common polymorphisms was determined in the 91 Caucasian cancer cases in this series and 24 sister controls using allele-specific amplification. The rare form of the Q356R polymorphism was significantly ( P = 0.03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk. In summary, our data suggest a role for some uncharacterized variants and rare forms of polymorphisms in determining ovarian cancer risk, and highlight the necessity to screen for missense alterations as well as truncating mutations in this population.