Faculty Bibliography

PURPOSE: Obesity has consistently been linked to an increased risk of colorectal cancer, particularly among men. Whether body mass index (BMI) differentially influences the risk across the stages of colorectal cancer development remains unclear. We evaluated the associations of BMI with colorectal adenoma incidence, adenoma recurrence, and cancer in the context of a large screening trial, in which cases and controls had an equal chance for disease detection. METHODS: We prospectively evaluated the association between baseline BMI and the risk of incident distal adenoma (1,213 cases), recurrent adenoma (752 cases), and incident colorectal cancer (966 cases) among men and women, ages 55 to 74 years, randomly assigned to receive flexible sigmoidoscopy screening as part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We calculated odds ratios (ORs) and 95% CIs for adenoma incidence and recurrence, and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence, using multivariable-adjusted models. RESULTS: Compared with normal-weight men (18.5 to 24.9 kg/m(2)), obese men (>/= 30 kg/m(2)) had significantly higher risk of incident adenoma (OR, 1.32; 95% CI, 1.06 to 1.65) and colorectal cancer (HR, 1.48; 95% CI, 1.16 to 1.89) and a borderline increased risk of recurrent adenoma (OR, 1.50; 95% CI, 0.98 to 2.30). No associations were observed for either adenoma or cancer in women. CONCLUSION: Data from this large prospective study suggest that obesity is important throughout the natural history of colorectal cancer, at least in men, and colorectal cancer prevention efforts should encourage the achievement and maintenance of a healthy body weight in addition to regular screenings.

It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymorphisms (SNPs) have been weakly associated with circulating concentrations of IGF-1 and IGF binding protein 3 (IGFBP-3), but none of these SNPs was associated with risk of prostate cancer. We examined whether an association between 16 SNPs associated with circulating IGF-1 or IGFBP-3 concentrations and prostate cancer exists within subgroups defined by dietary protein intake in 5,253 cases and 4,963 controls of European ancestry within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). The BPC3 includes nested case-control studies within large North-American and European cohorts. Per-allele odds ratios for prostate cancer for the SNPs were compared across tertiles of protein intake, which was expressed as the percentage of energy derived from total, animal, dairy or plant protein sources, using conditional logistic regression models. Total, animal, dairy and plant protein intakes were significantly positively associated with blood IGF-1 (p < 0.01), but not with IGFBP-3 concentrations (p > 0.10) or with risk of prostate cancer (p > 0.20). After adjusting for multiple testing, the SNP-prostate cancer associations did not differ by intakes of protein, although two interactions by intake of plant protein were of marginal statistical significance [SSTR5 (somatostatin receptor 5)-rs197056 (uncorrected p for interaction, 0.001); SSTR5-rs197057 (uncorrected p for interaction, 0.002)]. We found no strong evidence that the associations between 16 IGF pathway SNPs and prostate cancer differed by intakes of dietary protein.

We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P = .02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention.

Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (ORper T allele = 0.68, 95% CI: 0.57-0.83, P = 7.7 x 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (ORper T allele = 0.41, 95% CI: 0.30-0.55, P = 2.4 x 10(-) (9)) than for adenoma (ORper T allele = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (ORper T allele = 0.5, 95% CI: 0.37-0.69 and ORper T allele = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia.

BACKGROUND: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D. METHODS: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS). RESULTS: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately. CONCLUSIONS: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk. IMPACT: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. Cancer Epidemiol Biomarkers Prev; 22(11); 2037-46. (c)2013 AACR.

BACKGROUND: Formaldehyde, a widely used chemical, is considered a human carcinogen. METHODS: We extended follow-up of the largest industrial cohort of workers in formaldehyde industries (n = 25,619) by 10 years through 2004. Standardized mortality ratios (SMRs) and rate ratios (RRs) were calculated for deaths from solid tumors using quantitative formaldehyde exposure estimates. RESULTS: During 998,239 person-years, 13,951 deaths occurred. With one additional death, previously observed excesses for nasopharyngeal cancer (n = 10) persisted for peak, average intensity and cumulative exposure; RRs in the highest exposure categories were 7.66 (95% CI: 0.94, 62.34), P-trend = 0.005, 11.54 (95% CI: 1.38, 96.81), P-trend = 0.09, and 2.94 (95% CI: 0.65, 13.28), P-trend = 0.06, respectively. For all cancer, solid tumors and lung cancer, SMRs among exposed workers were elevated, but internal analyses revealed no positive associations with formaldehyde exposure. CONCLUSIONS: Consistent with previous analyses of this cohort, this update continues to suggest a link between formaldehyde exposure and nasopharyngeal cancer.

Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 x 10(-)(8)) near FTO (P = 3.72 x 10(-)(2)(3)), TMEM18 (P = 3.24 x 10(-)(1)(7)), MC4R (P = 4.41 x 10(-)(1)(7)), TNNI3K (P = 4.32 x 10(-)(1)(1)), SEC16B (P = 6.24 x 10(-)(9)), GNPDA2 (P = 1.11 x 10(-)(8)) and POMC (P = 4.94 x 10(-)(8)) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 x 10(-)(5) after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.