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Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses. Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR. Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses. Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development. Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development. [ABSTRACT FROM AUTHOR]

Background: The association between prediagnostic antibody responses to Fusobacterium nucleatum (F. nucleatum) and subsequent risk of colorectal cancer is not established. Methods: We conducted a nested case-control study of 8,126 participants in a consortium of 10 prospective cohorts in the United States. Results: Higher seroprevalence of any F. nucleatum antibody was observed among non-White participants (51.1%) compared with White participants (31.2%). We did not find any statistically significant association between seropositivity to any of the eight F. nucleatum proteins and colorectal cancer risk. Conclusions: Prediagnostic antibody responses to F. nucleatum proteins were not associated with the risk of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer. Methods: Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. Results: Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24). Conclusions: In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw. [ABSTRACT FROM AUTHOR]

Background: Prevalence of Helicobacter pylori (H. pylori) infection, the main risk factor for gastric cancer, has been decreasing in the United States; however, there remains a substantial racial disparity. Moreover, the time-trends for prevalence of CagA-positive H. pylori infection, the most virulent form, are unknown in the U.S. population. We sought to assess prevalence of CagA-positive H. pylori infection over time by race in the United States. Methods: We utilized multiplex serology to quantify antibody responses to H. pylori antigens in 4,476 participants across five cohorts that sampled adults from 1985 to 2009. Using log-binomial regression models, we calculated prevalence ratios and 95% confidence intervals for the association between H. pylori-CagA sero-prevalence and birth year by race. Results: African Americans were three times more likely to be H. pylori-CagA sero-positive than Whites. After adjustment, H. pylori-CagA sero-prevalence was lower with increasing birth year among Whites (Ptrend = 0.001), but remained stable for African Americans. When stratified by sex and education separately, the decline in H. pylori-CagA sero-positivity among Whites remained only for females (Ptrend < 0.001) and was independent of educational attainment. Among African Americans, there was no difference by sex; furthermore, sero-prevalence increased with increasing birth year among those with a high school education or less (P = 0.006). Conclusions: Among individuals in the United States born from the 1920s to 1960s, H. pylori-CagA sero-prevalence has declined among Whites, but not among African Americans. Impact: Our findings suggest a widening racial disparity in the prevalence of the most virulent form of H. pylori, the main cause of gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Telomeres play an important role in colorectal cancer prognosis. Variation in telomere maintenance genes may be associated with survival after colorectal cancer diagnosis, but evidence is limited. In addition, possible interactions between telomere maintenance genes and prognostic factors, such as smoking and sex, also remain to be investigated. Methods: We conducted gene-wide analyses of colorectal cancer prognosis in 4,896 invasive colorectal cancer cases from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); 1,871 common variants within 13 telomere maintenance genes were included. Cox models were fit to estimate associations of these variants individually with overall and colorectal cancer-specific survival. Likelihood ratio tests were used to test for interaction by smoking and sex. P values were adjusted using Bonferroni correction. Results: The association between minor allele of rs7200950 (ACD) with colorectal cancer-specific survival varied significantly by smoking pack-years (corrected P = 0.049), but no significant trend was observed. By sex, minor alleles for rs2975843 (TERF1), rs75676021 (POT1), and rs74429678 (POT1) were associated with decreased overall and/or colorectal cancer-specific survival in women but not in men. Conclusions: Our study reported a gene-wide statistically significant interaction with sex (TERF1, POT1). Although significant interaction by smoking pack-years (ACD) was observed, there was no evidence of a dose response. Validation of these findings in other large studies and further functional annotation on these SNPs are warranted. [ABSTRACT FROM AUTHOR]

Background: Antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG) proteins, especially pilus protein Gallo2178, have been consistently associated with colorectal cancer risk. Previous case-control studies and prospective studies with up to 8 years of follow-up, however, were unable to decipher the temporality of antibody responses to SGG in the context of the long-term multistep development of colorectal cancer. In this study, we analyzed a large U.S. colorectal cancer cohort consortium with follow-up beyond 10 years for antibody responses to SGG. Methods: We applied multiplex serology to measure antibody responses to 9 SGG proteins in participants of 10 prospective U.S. cohorts (CLUE, CPSII, HPFS, MEC, NHS, NYUWHS, PHS, PLCO, SCCS, and WHI) including 4,063 incident colorectal cancer cases and 4,063 matched controls. Conditional logistic regression was used to assess whether antibody responses to SGG were associated with colorectal cancer risk, overall and by time between blood draw and diagnosis. Results: Colorectal cancer risk was increased among those with antibody responses to Gallo2178, albeit not statistically significant [OR, 1.23; 95% confidence interval (CI), 0.99-1.52]. This association was stronger for cases diagnosed <10 years after blood draw (OR, 1.40; 95% CI, 1.09-1.79), but was not found among cases diagnosed =10 years after blood draw (OR, 0.79; 95% CI, 0.50-1.24). Conclusions: In a large cohort consortium, we reproduced the association of antibody responses to SGG Gallo2178 with colorectal cancer risk for individuals diagnosed within 10 years after blood draw. Impact: This timing-specific finding suggests that antibody responses to SGG are associated with increased colorectal cancer risk only after tumorigenesis has begun. [ABSTRACT FROM AUTHOR]

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. [ABSTRACT FROM AUTHOR]

Background: People with germline mutation in one of the DNA mismatch repair (MMR) genes have increased colorectal cancer risk. For these high-risk people, study findings of the relationship between alcohol consumption and colorectal cancer risk have been inconclusive. Methods: 1,925 MMR gene mutations carriers recruited into the Colon Cancer Family Registry who had completed a questionnaire on lifestyle factors were included. Weighted Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between alcohol consumption and colorectal cancer. Results: Colorectal cancer was diagnosed in 769 carriers (40%) at a mean (SD) age of 42.6 (10.3) years. Compared with abstention, ethanol consumption from any alcoholic beverage up to 14 g/day and >28 g/day was associated with increased colorectal cancer risk (HR, 1.50; 95% CI, 1.09-2.07 and 1.69; 95% CI, 1.07-2.65, respectively; Ptrend = 0.05), and colon cancer risk (HR, 1.78; 95% CI, 1.27-2.49 and 1.94; 95% CI, 1.19-3.18, respectively; Ptrend = 0.02). However, there was no clear evidence for an association with rectal cancer risk. Also, there was no evidence for associations between consumption of individual alcoholic beverage types (beer, wine, spirits) and colorectal, colon, or rectal cancer risk. Conclusions: Our data suggest that alcohol consumption, particularly more than 28 g/day of ethanol (~2 standard drinks of alcohol in the United States), is associated with increased colorectal cancer risk for MMR gene mutation carriers. Impact: Although these data suggested that alcohol consumption in MMR carriers was associated with increased colorectal cancer risk, there was no evidence of a dose-response, and not all types of alcohol consumption were associated with increased risk. [ABSTRACT FROM AUTHOR]

Background: Aspirin use is an effective strategy for the chemoprevention of colorectal cancer, even at low doses. However, in order to implement aspirin interventions, risk-benefit balances and biologic mechanisms need to be better defined; to further this aim, we used a metabolomics approach. Methods: We metabolically profiled 40 healthy, nonsmoking men and women ages 20 to 45 years enrolled in a randomized, double-blind, crossover trial of 325 mg aspirin/day over a period of 60 days. Gas and liquid chromatography-mass spectrometry were used to comprehensively profile participants' plasma samples after aspirin and placebo interventions. Results: A total of 363 metabolites, covering most human biochemical pathways, were measured. Compared with placebo- treated participants, plasma concentrations of the oncometabolite 2-hydroxyglutarate (RþS) decreased after aspirin treatment in both men and women (P = 0.005). This signal proved robust during 20-fold random splitting of the data using 80% of the samples in each split. We subsequently performed functional follow-up studies using targeted, enantiospecific detection in human colorectal cancer cell lines and observed an aspirininduced reduction of (R)-2-hydroxyglutarate. We further showed that salicylate, the primary aspirin metabolite, inhibits the hydroxyacid- oxoacid transhydrogenase mediated production of (R)-2- hydroxyglutarate, thereby providing mechanistic evidence for the clinically observed effects of aspirin on total-2-hydroxyglutarate. Conclusions: Using a metabolomics approach with functional follow-up, we propose that a decrease in the oncometabolite (R)- 2-hydroxyglutarate may identify an additional mechanism for aspirin or its metabolites in cancer prevention. Impact: Reduction of the oncometabolite (R)-2-hydroxyglutarate identifies a novel, non-COX-inhibition-mediated mechanism of aspirin. [ABSTRACT FROM AUTHOR]

Background: Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status. Methods: Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site. Results: Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52-0.96); associations were similar for colorectal cancer-specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics. Conclusion: Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active. Impact: Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer. [ABSTRACT FROM AUTHOR]

The article discusses a study related to relation between colorectal cancer and nonsteroidal anti-inflammatory drugs (NSAIDs). It states that there is substantial evidence that use of NSAIDs reduces the risk of colorectal cancer, but there is no identification for which the chemoprevention effect outweighs the risk of side effects.

The article discusses a research related to association between environmental exposures and incident colorectal cancer. It mentions several risk factors for colorectal cancer which include cigarette smoking, folate intake, and hormone therapy. It also mentions association of expression of estrogen receptor beta (ESR2) with colorectal cancer stage and survival.

The article discusses a research on nutritional epidemiology of cancer. It mentions that dietary epidemiology helps in preventing nutritional-deficiency conditions, revealing cardiovascular risk factors. It mentions a report by the organization World Cancer Research Fund (WCRF) on association between higher consumption of vegetables and fruit and lower risk of cancers of mouth and pharynx, esophagus and lung. It mentions association between dietary fat intake and breast cancer risk.

The article presents study on association of family history of colorectal cancer with colorectal cancer survival regardless of microsatellite instability status. It mentions the use of Cox proportional hazards regression to evaluate the association between family history and disease-specific survival. It adds that the study revealed no evidence of association between family history and overall hazard ratio (HR), confidence interval (CI), or disease-specific survival.

The article discusses a study which examined the role of cigarette smoking (CS), folate intake (FI) and hormone therapy (HT) on the development of colorectal cancer. Topics discussed include the analysis of TP53 protein expression level, an inverse association between longer HT duration and TP53 high colorectal cancer, and no statistically significant association found between TP53-specific colorectal cancer and CS and FI.

The article presents a study that determined telomere length from patients with colorectal cancer by comparing DNA preparation methods. The study examined PBL relative telomere length (RTL) measured by quantitative PCR and revealed the contribution of differences in DNA extraction method to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL.

The article discusses a study which examined the associations of family histories of diabetes and pancreatic cancer with risk of pancreatic cancer. Topics covered include how family history data were collected, the measures used for association analyses, and the need for studies of genetic influences on pancreatic cancer in large samples.

The article presents a study which examined the relationship between the family history of colorectal cancer (CRC) and extracolonic cancers (ECC) with the gene BRAF p.V600E mutation status of CRC. In the study, multivariable logistic regression were used to calculate odd ratios (OR) and confidence intervals (CI). The study suggested that inherited factors are more important in early-onset BRAF-wild-type CRC.

The article presents a study which analyzed the connection between the BRAF mutation and the survival of patients in Western Washington State diagnosed between 1997 and 2007 with invasive colorectal cancer. The study revealed that the prevalence of BRAF mutations in colorectal cancer varies by patient and tumor characteristics. Depending on the factors considered in the study, the connection between BRAF status and colorectal cancer survival differed.

The article presents a study which investigates the risk in colorectal cancer and postmenopausal hormone therapy (PHM) in relation to the status of somatic Kirsten RNA Associated Rat Sarcoma 2 Virus Gene (KRAS) mutation in older women. The study has recorded data of PMH therapy and other exposure at the baseline. Study shows the statistical insignificance of risk estimates in PHM therapy.

The article discusses a research study on oncogenic human papillomavirus (HPV) detection in colorectal tumors. Examined was the association of HPV infection and colorectal polyps in 167 patients with colorectal adenoma, 87 with hyperplastic polyps and 250 polyp-free controls through real-time polymerase chain reaction (PCR) assay. Conclusions indicated the absence of etiologic relationship between colorectal adenomas or hyperplastic polyps and HPV infection.

The article discusses the focus of the Asia Cohort Consortium Coordinating Center (ACC CC) on collaborative work, management of statistical data and tool development for cancer epidemiology research. It mentions funding for ACC CC activities granted by the Fred Hutchinson Cancer Research Center (FHCRC) for the mission of serving as incubator for new cohorts and platform for combined analysis of cross-cohort collaborative projects. It also notes the body mass index (BMI) project for Asians.

The author addresses the clues to carcinogenesis. According to the author, the environment is a determinant of developmental phenotype. He points out that there is a relationship between the biology of development and the biology of cancer. He adds that genotype sets limits on the phenotype and notes that there is marked plasticity within these limits.

The article discusses a study which examined the link between nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of prostate cancer among male members of the VITamins And Lifestyle cohort in Washington. Adjusted hazard ratios and confidence intervals were estimated using cox proportional hazards models. Findings revealed that low-dose aspiring, ibuprofen and any nonaspirin NSAID were not associated with risk of prostate cancer. In addition, regular-strength aspiring was shown to be inversely association with high-grade cancer risk.

The article discusses a study which examined the susceptibility locus for colorectal cancer on chromosome 9p24. Caucasians with colorectal adenoma or colorectal cancer and controls from four studies were included in the study. Results showed that single nucleotide polymorphisms (SNP) rs719725 was linked with colorectal cancer risk in Women's Health Initiative and was marginally associated with adenoma risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO).