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Complex diseases are often analyzed using disease subtypes classified by multiple biomarkers to study pathogenic heterogeneity. In such molecular pathological epidemiology research, we consider a weighted Cox proportional hazard model to evaluate the effect of exposures on various disease subtypes under competing‐risk settings in the presence of partially or completely missing biomarkers. The asymptotic properties of the inverse and augmented inverse probability‐weighted estimating equation methods are studied with a general pattern of missing data. Simulation studies have been conducted to demonstrate the double robustness of the estimators. For illustration, we applied this method to examine the association between pack‐years of smoking before the age of 30 and the incidence of colorectal cancer subtypes defined by a combination of four tumor molecular biomarkers (statuses of microsatellite instability, CpG island methylator phenotype, BRAF mutation, and KRAS mutation) in the Nurses' Health Study cohort. [ABSTRACT FROM AUTHOR]

Background: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. Methods: Among 2424 patients with stage I–III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow‐up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all‐cause and CRC‐specific mortality according to post‐diagnostic use and dose of multivitamin supplements. Results: During a median follow‐up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non‐users, post‐diagnostic users of multivitamin supplements at a dose of 3–5 tablets/week had lower CRC‐specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36–0.83, p =.005), and post‐diagnostic users at doses of 3–5 and 6–9 tablets/week had lower all‐cause mortality (HR, 0.81; 95% CI, 0.67–0.99, p =.04; HR, 0.79; 95% CI, 0.70–0.88), p <.001). The dose–response analysis showed a curvilinear relationship for both CRC‐specific (pnonlinearity <.001) and all‐cause mortality (pnonlinearity =.004), with the maximum risk reduction observed at 3–5 tablets/week and no further reduction at higher doses. Compared to non‐users in both pre‐ and post‐diagnosis periods, new post‐diagnostic users at dose of <10 tablets/week had a lower all‐cause mortality (HR, 0.81; 95% CI, 0.71–0.94, p =.005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07–2.33) and discontinued users (HR, 1.35; 95% CI, 1.14–1.59) had a higher risk of mortality. Conclusions: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC‐specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC‐specific mortality. In this prospective study of 2424 patients with stage I–III colorectal cancer (CRC), the authors observed a curvilinear relationship in the use of multivitamin supplements: compared to non‐users, users at a dose of 3–9 tablets/week had a lower risk of CRC‐specific and all‐cause mortality, whereas users at a dose higher than 10 tablets/week had a higher CRC‐specific mortality. [ABSTRACT FROM AUTHOR]

It remains unknown whether maintenance of a healthy lifestyle after endoscopic polypectomy could still confer benefit for colorectal cancer (CRC) incidence and mortality. In this study, we defined a healthy lifestyle score based on body mass index, smoking, physical activity, alcohol consumption and diet (range, 0‐5). We used Cox proportional hazards regression to estimate the hazard ratios (HRs) for the associations of healthy lifestyle score and individual lifestyle factors with CRC incidence and all‐cause mortality. During a median of 10 years of follow‐up of 24 668 participants who underwent endoscopic polypectomy, we documented 161 CRC cases and 4857 all‐cause deaths. A higher healthy lifestyle score after endoscopic polypectomy was associated with lower risk of CRC and all‐cause mortality. Compared with individuals with 0 to 1 healthy lifestyle factors, those with 2, 3 and 4 to 5 healthy lifestyle factors had a HR for CRC risk of 0.86 (95% confidence interval [CI], 0.60‐1.24), 0.73 (95% CI, 0.47‐1.14) and 0.52 (95% CI, 0.27‐1.01), respectively (Ptrend =.03). The corresponding HR (95% CI) for all‐cause mortality was 0.83 (95% CI, 0.76‐0.90), 0.63 (95% CI, 0.56‐0.70) and 0.56 (95% CI, 0.48‐0.65), respectively (Ptrend <.0001). In the joint analysis of pre‐ and postpolypectomy periods, patients with a healthy postpolypectomy lifestyle had a lower incidence of CRC regardless of their prepolypectomy exposure, whereas those with a healthy lifestyle in both periods had a lower mortality than those with an unhealthy lifestyle in either period. In conclusion, adherence to a healthy lifestyle after polypectomy may confer significant benefit for CRC prevention and reduction in all‐cause mortality. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) have a unique favorable effect on the prognosis of colorectal cancer (CRC), although their association with stage‐specific outcomes remains unclear. We assessed the densities of CD68+ and CD163+ TAMs at the invasive front of resected CRC stage III CRC from 236 patients, 165 of whom received post‐surgical FOLFOX treatment, and their relationship with disease‐free survival (DFS). Associations between macrophage mRNAs and clinical outcome were investigated in silico in 59 stage III CRC and FOLFOX‐treated patients from The Cancer Genome Atlas (TCGA). Biological interactions of SW480 and HT29 cells and macrophages with FOLFOX were tested in co‐culture models. Low TAM densities were associated with shorter DFS among patients receiving FOLFOX (CD68+, p = 0.0001; CD163+, p = 0.0008) but not among those who were untreated. By multivariate Cox analysis, only low TAM (CD68+, p = 0.001; CD163+, p = 0.002) and nodal status (CD68+, p = 0.009; CD163+, p = 0.007) maintained an independent predictive value. In the TCGA cohort, high CD68 mRNA levels were associated with better outcome (p = 0.02). Macrophages enhanced FOLFOX cytotoxicity on CRC cells (p < 0.01), and drugs oriented macrophage polarization from M2‐ to M1‐phenotype. Low TAM densities identify stage III CRC patients at higher risk of recurrence after adjuvant therapy, and macrophages can augment the chemo‐sensitivity of micro‐metastases. [ABSTRACT FROM AUTHOR]

Two messenger RNA (mRNA) vaccines developed by Pfizer‐BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID‐19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID‐19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID‐19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID‐19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID‐19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47–65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62–24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain‐Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real‐world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines. [ABSTRACT FROM AUTHOR]

Summary: The coronavirus disease (Covid‐19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter‐individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome‐associated coronavirus, severe acute respiratory syndrome‐associated coronavirus‐2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti‐inflammatory cytokines and might modulate the progression of Covid‐19 in affected patients. Notably, genetic variations in innate immune components such as toll‐like receptors and mannose‐binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner. [ABSTRACT FROM AUTHOR]

Most risk prediction models for colorectal cancer (CRC) are based on questionnaires and show a modest discriminatory ability. Therefore, we aim to develop risk prediction models incorporating plasma biomarkers for CRC to improve discrimination. We assessed the predictivity of 11 biomarkers in 736 men in the Health Professionals Follow‐up Study and 639 women in the Nurses' Health Study. We used stepwise logistic regression to examine whether a set of biomarkers improved the predictivity on the basis of predictors in the National Cancer Institute's (NCI) Colorectal Cancer Risk Assessment Tool. Model discrimination was assessed using C‐statistics. Bootstrap with 500 randomly sampled replicates was used for internal validation. The models containing each biomarker generated a C‐statistic ranging from 0.50 to 0.59 in men and 0.50 to 0.54 in women. The NCI model demonstrated a C‐statistic (95% CI) of 0.67 (0.62‐0.71) in men and 0.58 (0.54‐0.63) in women. Through stepwise selection of biomarkers, the C‐statistic increased to 0.70 (0.66‐0.74) in men after adding growth/differentiation factor 15, total adiponectin, sex hormone binding globulin and tumor necrosis factor receptor superfamily member 1B (P for difference = 0.008); and increased to 0.62 (0.57‐0.66) in women after further including insulin‐like growth factor 1 and insulin‐like growth factor‐binding protein 3 (P for difference =.06). The NCI + selected biomarkers model was internally validated with a C‐statistic (95% CI) of 0.73 (0.70‐0.77) in men and 0.66 (0.61‐0.70) in women. Circulating plasma biomarkers may improve the performance of risk factor‐based prediction model for CRC. What's new? Most risk prediction models for colorectal cancer are based on questionnaires and have shown a modest discriminatory ability. Based on data from two U.S. cohorts, here the authors present a risk prediction model using questionnaire information and plasma biomarker measurements. Adding growth/differentiation factor 15, total adiponectin, sex hormone binding globulin, and tumour necrosis factor receptor superfamily member 1B for men and insulin‐like growth factor 1 and insulin‐like growth factor‐binding protein 3 for women slightly increased the discriminatory accuracy. These results provide proof of principle for the inclusion of biomarkers into colorectal cancer risk assessment to improve early detection and surveillance. [ABSTRACT FROM AUTHOR]

The influence of polyunsaturated fatty acids (PUFAs) on risk of colorectal cancer precursors remains largely unknown. We examined the associations of erythrocyte PUFAs, including n−3 and n−6 PUFAs, with risk of colorectal conventional adenomas and serrated polyps in 4517 participants from three US prospective cohorts who had provided a blood sample and undergone at least one endoscopic examination. We calculated the multivariable odds ratios (ORs) per 1 SD increment in individual PUFAs and the ratio of n−6/n−3 PUFAs. We considered P <.005 statistically significant to account for multiple testing. During a median of 20 years of follow‐up, we documented 493 conventional adenomas and 316 serrated polyps. After adjusting for various CRC risk factors, no associations for PUFAs achieved the stringent statistical significance for either conventional adenomas or serrated polyps (ORs per 1 SD ranged from 0.90 to 1.14). Some associations achieved nominal significance (P <.05), including the association of dihomogammalinolenic acid (DGLA) (20:3, n−6) with lower risk of conventional adenomas (OR = 0.91; 95% confidence interval [CI] = 0.83‐1.00), total n−6 PUFAs with higher risk of proximal serrated polyps (OR = 1.32; 95% CI = 1.01‐1.74) and eicosadienoic acid (20:2, n−6) and DGLA with lower risk of advanced adenomas (OR = 0.83; 95% CI = 0.71‐0.97 and OR = 0.84; 95% CI = 0.72‐0.98, respectively). Our findings indicate that erythrocyte PUFAs in a typical American diet are unlikely to have a substantial influence on risk of colorectal cancer precursors. The subgroup associations require further confirmation. What's new? The influence of polyunsaturated fatty acids on risk of colorectal cancer precursors remains largely unknown. Over a median follow‐up duration of 20 years, this prospective study examined the associations of erythrocyte n‐3 and n‐6 polyunsaturated fatty acids with risk of colorectal cancer precursors in three large prospective cohorts in the United States. No statistically significant association was found at α=0.005 level for any of the fatty acids with either conventional adenomas or serrated polyps. The findings indicate that n‐3 and n‐6 polyunsaturated fatty acids in a typical American diet are unlikely to have a substantial impact on colorectal cancer precursors. [ABSTRACT FROM AUTHOR]

Serrated polyps (SPs) and conventional adenomas represent 2 distinct groups of colorectal premalignancy. The influence of early life adiposity on risk of these precursors remains unclear. Within the Nurses' Health Study, the Nurses' Health Study 2, and the Health Professionals Follow‐up Study, we assessed body fatness during childhood using 9‐level somatotype and obtained weight and body mass index (BMI) in adulthood. We used multivariable‐adjusted logistic regression to examine the association of SPs and conventional adenomas with body fatness in early childhood (age 5), late childhood (age 10), early adulthood (age 18/21) and middle adulthood (baseline) and weight change during early‐to‐middle adulthood. During 18–20 years of follow‐up, we documented 8,697 SPs and 10,219 conventional adenomas in 132,514 women; 2,403 SPs and 4,495 conventional adenomas in 29,207 men. We found a modest positive association of adiposity in early and late childhood with risk of SPs and conventional adenomas, with odds ratios ranging from 1.12 to 1.18 for comparison of extreme somatotypes groups. The associations were attenuated after adjusting for adulthood BMI but remained significant for conventional adenomas. No association with early life body fatness was found in men. Adulthood body fatness and weight change during early‐to‐middle adulthood showed positive relationships with SPs and conventional adenomas in both women and men, with stronger associations observed for SPs (pheterogeneity < 0.0001). Our findings indicated a potential role in development of colorectal cancer precursors of childhood body fatness in women, and early‐to‐middle adulthood weight gain and attained adiposity in both sexes. What's new? Being overweight in childhood may increase the risk of colon cancer in adulthood. Here, the authors set out to quantify the effect of childhood adiposity on the risk of 2 different colorectal cancer precursors, serrated polyps and conventional adenomas. They collected data on body mass from various points throughout people's lifetime. Excess fat in early and late childhood had a small positive association with risk of serrated polyps and conventional adenomas in women, with odds ratios between 1.12‐1.28. These findings suggest that childhood obesity could lay the groundwork for the formation of colorectal cancer precursors. [ABSTRACT FROM AUTHOR]

Anthropometric measurements, such as body mass index (BMI), waist circumference, and body fat percentage, have been used as indicators of obesity. Despite evidence that excess body fat is a risk factor for colorectal carcinoma (CRC), the magnitude of the association of BMI and other obesity indicators with the long‐term risk of CRC remains unclear. Utilizing a Cox proportional hazards regression model, we examined differential associations between predicted body fat percentage and BMI with the risk of CRC (n = 2,017). The associations between CRC incidence and different adiposity measurements were also assessed. Predicted body fat percentage had a similar increased risk of CRC risk as BMI. In multivariable‐adjusted analyses, the hazard ratio for CRC in the second to fifth quintiles (compared to the first quintile) of predicted body fat percentage were 1.32, 1.31, 1.53 and 2.09 for men (ptrend < 0.001) and 0.91, 0.90, 0.98 and 1.15 for women (ptrend = 0.03). Among various anthropometric measurements, predicted fat mass and waist circumference were slightly more strongly associated with CRC risk than BMI. In conclusion, the novel anthropometric prediction equations provided further evidence that a greater amount of body fat might contribute to CRC risk in both sexes. An innovative approach enabled us to estimate the susceptibilities of specific body composition with CRC risk, in an inexpensive and minimally invasive manner. Furthermore, the typically used measures of BMI and waist circumference are robust measures of adiposity to predict cancer risk in a relatively healthy population. What's new? While excess body fat is linked to increased colorectal cancer (CRC) risk, the degree to which specific factors, such as body mass index (BMI) and waist circumference, predict long‐term CRC risk is unclear. In this investigation, data from two U.S. prospective cohorts and novel anthropometric prediction equations highly correlated with dual‐energy X‐ray absorptiometry measures were used to examine the long‐term influence of specific body composition on CRC risk. Analyses show that predicted body fat percentage and BMI share similar associations with CRC risk in both sexes. Hence, no marked heterogeneity was observed in CRC risk estimation across adiposity measures. [ABSTRACT FROM AUTHOR]

Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are limited on different food sources of fiber and heterogeneity by tumor subsite and molecular profile. We prospectively followed for CRC incidence 90,869 women from the Nurses' Health Study (1980–2012) and 47,924 men from the Health Professionals Follow‐up Study (1986–2012), who completed a validated food frequency questionnaire every 4 years. Cox proportional hazards regression was used to examine the associations with CRC risk for total, cereal, fruit and vegetable fiber and whole grains. We also assessed the associations according to tumor subsites (proximal colon, distal colon and rectum) and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype and KRAS mutation). We documented 3,178 CRC cases during 3,685,903 person‐years of follow‐up in the NHS and HPFS. Intake of total dietary fiber was not associated with CRC risk after multivariable adjustment in either women (hazard ratio [HR] comparing extreme deciles, 1.17; 95% CI, 0.92–1.48, ptrend = 0.55) or men (HR, 0.90; 95% CI, 0.67–1.21, ptrend = 0.47). Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men with an HR of 0.75 (95% CI, 0.57–1.00) and 0.72 (95% CI, 0.54–0.96), respectively. No heterogeneity was detected by tumor subsite or molecular markers (pheterogeneity > 0.05). Higher intake of total dietary fiber within the range of a typical American diet is unlikely to substantially reduce CRC risk. The potential benefit of cereal fiber and whole grains in men warrants further confirmation. What's new? Epidemiologic evidence relating fiber intake to colorectal cancer (CRC) remains inconclusive and data are still limited on different food sources and heterogeneity by tumor subsite and molecular profile. Here, total dietary fiber intake within the range of a typical American diet was not found to be associated with CRC risk after adjusting for other dietary and lifestyle factors. Higher intake of cereal fiber and whole grains was associated with lower CRC risk in men. Associations of dietary fiber and CRC did not vary by tumor subsites and molecular markers (microsatellite instability, BRAF mutation, CpG island methylator phenotype, and KRAS mutation). [ABSTRACT FROM AUTHOR]

Molecular pathological epidemiology (MPE) is an integrative transdisciplinary field that addresses heterogeneous effects of exogenous and endogenous factors (collectively termed 'exposures'), including microorganisms, on disease occurrence and consequences, utilising molecular pathological signatures of the disease. In parallel with the paradigm of precision medicine, findings from MPE research can provide aetiological insights into tailored strategies of disease prevention and treatment. Due to the availability of molecular pathological tests on tumours, the MPE approach has been utilised predominantly in research on cancers including breast, lung, prostate, and colorectal carcinomas. Mounting evidence indicates that the microbiome (inclusive of viruses, bacteria, fungi, and parasites) plays an important role in a variety of human diseases including neoplasms. An alteration of the microbiome may be not only a cause of neoplasia but also an informative biomarker that indicates or mediates the association of an epidemiological exposure with health conditions and outcomes. To adequately educate and train investigators in this emerging area, we herein propose the integration of microbiology into the MPE model (termed 'microbiology‐MPE'), which could improve our understanding of the complex interactions of environment, tumour cells, the immune system, and microbes in the tumour microenvironment during the carcinogenic process. Using this approach, we can examine how lifestyle factors, dietary patterns, medications, environmental exposures, and germline genetics influence cancer development and progression through impacting the microbial communities in the human body. Further integration of other disciplines (e.g. pharmacology, immunology, nutrition) into microbiology‐MPE would expand this developing research frontier. With the advent of high‐throughput next‐generation sequencing technologies, researchers now have increasing access to large‐scale metagenomics as well as other omics data (e.g. genomics, epigenomics, proteomics, and metabolomics) in population‐based research. The integrative field of microbiology‐MPE will open new opportunities for personalised medicine and public health. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Periodontal diseases including tooth loss might increase systemic inflammation, lead to immune dysregulation and alter gut microbiota, thereby possibly influencing colorectal carcinogenesis. Few epidemiological studies have examined the association between periodontal diseases and colorectal cancer (CRC) risk. We collected information on the periodontal disease (defined as history of periodontal bone loss) and number of natural teeth in the Nurses' Health Study. A total of 77,443 women were followed since 1992. We used Cox proportional hazard models to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjustment for smoking and other known risk factors for CRC. We documented 1,165 incident CRC through 2010. Compared to women with 25-32 teeth, the multivariable HR (95% CI) for CRC for women with <17 teeth was 1.20 (1.04-1.39). With regard to tumor site, the HRs (95% CIs) for the same comparison were 1.23 (1.01-1.51) for proximal colon cancer, 1.03 (0.76-1.38) for distal colon cancer and 1.48 (1.07-2.05) for rectal cancer. In addition, compared to those without periodontal disease, HRs for CRC were 0.91 (95% CI 0.74-1.12) for periodontal disease, and 1.22 (95% CI 0.91-1.63) when limited to moderate to severe periodontal disease. The results were not modified by smoking status, body mass index or alcohol consumption. Women with fewer teeth, possibly moderate or severe periodontal disease, might be at a modest increased risk of developing CRC, suggesting a potential role of oral health in colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

The relationship between calcium intake and colorectal cancer (CRC) risk remains inconclusive. We conducted this study to evaluate whether the association between calcium intake and CRC risk differs by anatomic subsite and determine the dose-response relationship for this association, as well as assess when in carcinogenesis calcium may play a role. We assessed calcium intake every 4 years and followed 88,509 women (1980-2012) in the Nurses' Health Study and 47,740 men (1986-2012) in the Health Professionals Follow-Up Study. We documented 3,078 incident CRC cases. Total calcium intake (≥1,400 vs. <600 mg/d) was associated with a statistically significant lower risk of colon cancer (multivariable relative risk: 0.78, 95%CI: 0.65-0.95). Similar results were observed by different sources of calcium (from all foods or dairy products only). The inverse association was linear and suggestively stronger for distal colon cancer (0.65, 0.43-0.99) than for proximal colon cancer (0.94, 0.72-1.22, p-common effects = 0.14). Additionally, when comparing different latencies, the overall pattern suggested that the inverse association appeared to be stronger with increasing latency and was strongest for intakes 12-16 years before diagnosis. Comparing total calcium intakes of ≥1,400 vs. <600 mg/d for intake 12-16 y before diagnosis, the pooled RR (95% CIs) of CRC was 0.76 (0.64-0.91). Higher calcium intake was associated with a lower risk of developing colon cancer, especially for distal colon cancer. Overall inverse association was linear and did not differ by intake source. Additionally, calcium intake approximately 10 years before diagnosis appeared to be associated with a lower risk of CRC. [ABSTRACT FROM AUTHOR]

Vitamin B2 serves as a cofactor to enhance one-carbon metabolism, maintain mucous membranes, and has been implicated in lowering colorectal cancer (CRC) risk. However, few prospective studies have examined the association between vitamin B2 intake and CRC. In this study, we estimated the associations between vitamin B2 intake and CRC risk using the Nurses' Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) cohorts. Vitamin B2 intake was measured by a validated food frequency questionnaire every 4 years. Among 100,033 women in the NHS and 44,007 men in the HPFS we documented a total of 3,037 incident CRC cases (2,093 women and 944 men) during 24-26 years of follow-up until 2010. Intakes of total (from food and supplements), dietary (from food only), and supplemental vitamin B2 were inversely related to CRC risk in age-adjusted analysis in NHS. However, the association was attenuated and no longer statistically significant in multivariate analysis ( p-trend ≥0.08). The pooled multivariate relative risks (95% confidence interval) comparing individuals in the extreme quintiles of intakes were 0.93 (0.81-1.06) for total vitamin B2, 0.89 (0.61-1.28) for dietary vitamin B2 and 0.94 (0.81-1.08) for supplemental vitamin B2. These associations of total vitamin B2 intake were similar for risk of CRC with varying lag-time periods (0-4, 4-8, 8-12 or 12-16 years), for risk of CRC subtypes by tumor location, and across strata of intake of folate or alcohol. Our prospective data do not support a beneficial role of vitamin B2 intake in lowering incidence of CRC. [ABSTRACT FROM AUTHOR]

Higher body mass index (BMI), higher body adiposity and obesity have been associated with increased risk of colorectal cancer. Evidence suggests that excess energy balance may influence systemic immune and inflammatory status. Thus, we hypothesized that the positive association between BMI and colorectal cancer risk might differ according to colorectal carcinoma subtypes according to levels of histopathological lymphocytic reaction to tumor. We collected biennial questionnaire data on weight and baseline height information in two prospective cohort studies, the Nurses' Health Study (1980-2010) and the Health Professionals Follow-up Study (1986-2010). Utilizing duplication-method Cox proportional hazards regression models, we prospectively assessed the association between BMI and risk of colorectal cancer subtypes according to the degree of Crohn's-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, the overall lymphocytic reaction score, or T-cell [CD3+, CD8+, CD45RO (PTPRC)+ or FOXP3+] density in tumor tissue. Statistical significance level was adjusted for multiple hypotheses testing by Bonferroni correction. During follow up of 1,708,029 men and women (over 3,346,752 person-years), we documented 1,436 incident rectal and colon cancer cases with available formalin-fixed paraffin-embedded tumor tissue materials and pathological immunity data. BMI was significantly associated with higher risk of overall colorectal cancer (Ptrend < 0.001); however, the association of BMI with colorectal carcinoma risk did not significantly differ by the level of lymphocytic reaction or T-cell infiltration in tumor tissue status (Pheterogeneity > 0.10). BMI may be associated with risk of colorectal cancer regardless of levels of lymphocytic response to tumor. [ABSTRACT FROM AUTHOR]

A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available. [ABSTRACT FROM AUTHOR]

Circulating adiponectin has been associated with lower risk of colorectal cancer (CRC). Genome-wide association studies have identified several single-nucleotide polymorphisms (SNPs) associated with adiponectin levels. However, it is unclear whether these SNPs are associated with CRC risk. In addition, previous data on SNPs in the adiponectin pathway and their associations with CRC are inconsistent. Therefore, we examined 19 SNPs in genes related to adiponectin or its receptors and their associations with CRC using logistic regression among 7,020 cases and 7,631 controls drawn from ten studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium. Using data from a subset of two large cohort studies, we also assessed the contribution of individual SNPs and an adiponectin genetic score to plasma adiponectin after accounting for lifestyle factors among 2,217 women and 619 men. We did not find any statistically significant association between the 19 adiponectin-associated SNPs and CRC risk (multivariable-adjusted odds ratios ranged from 0.89 to 1.05, all p > 0.05). Each SNP explained less than 2.50% of the variance of plasma adiponectin, and the genetic score collectively accounted for 2.95 and 1.42% of the variability of adiponectin in women and men, respectively, after adjustment for age, body mass index, physical activity, smoking, alcohol consumption, regular use of aspirin or nonsteroidal anti-inflammatory drug and postmenopausal hormone use. In conclusion, our findings do not support an association between known adiponectin-related common SNPs and CRC incidence. However, known common SNPs account for only a limited proportion of the interindividual variance in circulating adiponectin. Further work is warranted to investigate the relationship between adiponectin and CRC while accounting for other components in the pathway. [ABSTRACT FROM AUTHOR]

The association between fish, ω-3 and ω-6 polyunsaturated fatty acid (PUFA) intake and risk of colorectal cancer (CRC) remains inconclusive. Recent prospective studies suggest that the relationship may vary by gender, subsite and duration of follow-up. We followed 123,529 US adults (76,386 women and 47,143 men) without a history of cancer at baseline for 24 to 26 years. Fish and PUFA intake was assessed at baseline and updated every 4 years by using a validated food-frequency questionnaire. We found no overall association between fish, ω-3 and ω-6 PUFA intake and CRC risk with hazard ratio (HR) of 1.03 [95% confidence interval (CI): 0.89-1.20] comparing marine ω-3 intake of ≥0.30 g/d versus <0.15 g/d among women and 1.05 (95% CI: 0.85-1.30) comparing intake of ≥0.41 g/d versus <0.16 g/d among men. However, fish and marine ω-3 PUFA intake appeared to be positively associated with risk of distal colon cancer in both men and women and inversely with risk of rectal cancer in men. In an analysis based on a limited number of cases, marine ω-3 PUFA intake assessed 12-16 years before diagnosis tended to be inversely associated with CRC risk in men (HR: 0.76; 95% CI: 0.52-1.10). In conclusion, although no overall association between fish, ω-3 or ω-6 PUFA intake was observed with CRC risk, marine ω-3 PUFA may be differentially associated with risk of distal colon and rectal cancers and a long latency may be needed for its protection against CRC in men. [ABSTRACT FROM AUTHOR]

Adolescent diet may be etiologically relevant for later risk of colorectal adenoma, a precursor of colorectal cancer. We aimed to examine associations between adolescent dietary patterns (derived using factor analysis) and risk of colorectal adenoma in middle adulthood. We analyzed data from 17,221 women participating in the Nurses' Health Study II, who had completed a validated high school (HS) food frequency questionnaire in 1998 when they were 34-51 years old, and had subsequently undergone at least one lower bowel endoscopy. Between 1998 and 2007, 1,299 women were diagnosed with at least one colorectal adenoma. In multivariable models adjusted for adult dietary patterns, a higher 'prudent' pattern during HS, characterized by high consumption of vegetables, fruit and fish was associated with a statistically significantly lower risk of rectal (odds ratio [OR] highest vs. lowest quintile, 0.45, 95% CI 0.27-0.75, p-trend = 0.005), but not colon adenomas. A higher 'Western' pattern during HS, characterized by high consumption of desserts and sweets, snack foods and red and processed meat, was significantly associated with rectal (OR 1.78, 95% CI 1.12-2.85, p-trend = 0.005) and advanced (OR 1.58, 95% CI 1.07-2.33, p-trend = 0.08), but not associated with colon or non-advanced adenomas. This study suggests that overall eating patterns during high school may influence later risk of rectal and advanced adenoma, independent of adult diet. Our results support the hypothesis that diet during early life may influence colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND Individuals with a history of colorectal cancer (CRC) have an increased risk of subsequent cancer. In this study, the authors used cancer registry data to evaluate whether this increased risk of cancer after CRC differed by anatomic subsite of a first CRC. METHODS Individuals diagnosed with a first primary CRC between 1992 and 2009 were identified from 12 Surveillance, Epidemiology, and End Results (SEER) cancer registries. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing the incidence of subsequent cancers in these patients who had an index CRC versus the cancer incidence rates in the general population. SIRs were calculated for cancers at anatomic sites within and outside the colorectum in analyses stratified by subsite of the index CRC. RESULTS Cancer incidence rates were significantly higher in individuals who had a previous CRC than in the general population (SIR, 1.15; 95% CI, 1.13-1.16). Individuals with an index CRC located between the transverse and descending colon experienced the greatest increased risk both overall (SIR, 1.29-1.33) and particularly with respect to the risk of a second CRC (SIR, 2.53-3.35). The incidence of small intestinal cancer was elevated significantly regardless of the index CRC subsite (SIR, 4.31; 95% CI, 3.70-4.77), and the incidence of endometrial cancer was elevated in those who had an index CRC in the proximal colon (SIR, 1.37-1.79). CONCLUSIONS The risk of second cancer after CRC differs by anatomic site of the first tumor and is particularly pronounced for those with prior CRC located in the transverse to descending colon. The mechanisms underlying this pattern of second cancer risk remain unknown. Cancer 2013;119:3140-3147. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Inactivation of the TP53 (p53) pathway by TP53 mutations is one of key steps in colorectal carcinogenesis. TP53 also plays an important role in cellular energy metabolism. We hypothesized that TP53-altered tumor cells might behave aggressively independent of energy balance, while progression of TP53-intact cells might depend on excess energy balance. Utilizing a database of 1,060 colon and rectal cancer patients in two prospective cohort studies, we evaluated TP53 expression by immunohistochemistry. Among 1,060 colorectal cancers, 457 (43%) tumors were positive for TP53. Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for clinical and tumoral features, including microsatellite instability, the CpG island methylator phenotype, LINE-1 methylation, KRAS, BRAF and PIK3CA. TP53 positivity was not significantly associated with cancer-specific survival in univariate analysis with HR of 1.16 [95% confidence interval (CI) = 0.92-1.45], which became significant after stage adjustment (multivariate HR = 1.30; 95% CI = 1.02-1.65). Notably, we found a possible modifying effect of patient's body mass index (BMI) on tumor TP53. In non-obese patients (BMI < 30 kg/m2), TP53 positivity was associated with shorter cancer-specific survival (multivariate HR = 1.53; 95% CI = 1.17-2.00), while TP53 positivity was not significantly associated with survival among obese patients (BMI ≥30 kg/m2). Effect of TP53 positivity on cancer-specific survival significantly differed by BMI ( pinteraction = 0.0051). The adverse effect of obesity on patient mortality was limited to TP53-negative patients. These molecular pathological epidemiology data may support a dual role of TP53 alterations in cell-cycle deregulation and cell autonomy with respect to energy balance status. [ABSTRACT FROM AUTHOR]

The article focuses on a study about the association between phosphorylated (p)-AKT expression with PIK3CA mutation and low stage and favorable prognosis of colorectal cancer. It relates the processes behind the study, one is the collection of tissue blocks from hospitals. Results of the study reinforce such association, leading to the suggestion that p-AKT can serve as a biomarker for outcomes and therapeutic targets. Factors behind the relationship between AKT activation and positive prognosis are discussed.

A cyclin-dependent kinase inhibitor CDKN2A (p16/Ink4a) is a tumor suppressor and upregulated in cellular senescence. CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype (CIMP) in colon cancer. However, prognostic significance of CDKN2A methylation or loss of CDKN2A (p16) expression independent of CIMP status remains uncertain. Using a database of 902 colorectal cancers in 2 independent cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study), we quantified CDKN2A promoter methylation and detected hypermethylation in 269 tumors (30%). By immunohistochemistry, we detected loss of CDKN2A (p16) expression in 25% (200/804) of tumors. We analyzed for LINE-1 hypomethylation and hypermethylation at 7 CIMP-specific CpG islands (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); microsatellite instability (MSI); KRAS, BRAF and PIK3CA mutations; and expression of TP53 (p53), CTNNB1 (β-catenin), CDKN1A (p21), CDKN1B (p27), CCND1 (cyclin D1), FASN (fatty acid synthase) and PTGS2 (cyclooxygenase-2). CDKN2A promoter methylation and loss of CDKN2A (p16) were associated with shorter overall survival in univariate Cox regression analysis [hazard ratio (HR): 1.36, 95% CI: 1.10-1.66, p = 0.0036 for CDKN2A methylation; HR: 1.30, 95% CI: 1.03-1.63, p = 0.026 for CDKN2A (p16) loss] but not in multivariate analysis that adjusted for clinical and tumor variables, including CIMP, MSI and LINE-1 methylation. Neither CDKN2A promoter methylation nor loss of CDKN2A (p16) was associated with colorectal cancer-specific mortality in uni- or multivariate analysis. Despite its well-established role in carcinogenesis, CDKN2A (p16) promoter methylation or loss of expression in colorectal cancer is not independently associated with patient prognosis. [ABSTRACT FROM AUTHOR]

The abundance of tumour-infiltrating T-cells has been associated with microsatellite instability (MSI) and a favourable prognosis in colorectal cancer. However, numerous molecular alterations have been associated with clinical outcome, and potentially confounding the biological and prognostic significance of tumour-infiltrating T-cells. We utilized a database of clinically and molecularly-annotated colon and rectal carcinoma cases ( N = 768; stage I-IV) in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study) and quantified the densities of CD3+, CD8+, CD45RO+ ( PTPRC), and FOXP3+ cells within neoplastic epithelial areas using an Ariol image analysis system and tissue microarray. We used Cox proportional hazard models to compute the mortality hazard ratio, adjusting for clinical and molecular features including KRAS, BRAF, and PIK3CA mutations, MSI, CIMP, and LINE-1 hypomethylation. The densities of CD8+, CD45RO+, and FOXP3+ cells were significantly associated with patient survival in univariate analyses ( $p_{\rm{trend}} < 0.007$). In the multivariate model, tumour-infiltrating CD45RO+-cell density, but not CD3+, CD8+ or FOXP3+-cell density, was significantly associated with survival ( p = 0.0032). In multivariate linear regression analysis, MSI-high ( p < 0.0001) and high-level tumour LINE-1 methylation ( p = 0.0013) were independently associated with higher CD45RO+-cell density. The survival benefit associated with CD45RO+ cells was independent of MSI and LINE-1 status. In conclusion, tumour-infiltrating CD45RO+-cell density is a prognostic biomarker associated with longer survival of colorectal cancer patients, independent of clinical, pathological, and molecular features. In addition, MSI-high and tumour LINE-1 methylation level are independent predictors of CD45RO+-cell density. Our data offer a possible mechanism by which MSI confers an improved clinical outcome and support efforts to augment the host immune response in the tumour microenvironment as a strategy of targeted immunotherapy. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Alterations in the Wnt/β-catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin-dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for β-catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including β-catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with β-catenin activation ( p = 0.0002), female gender ( p < 0.0001) and FASN overexpression ( p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer-specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03-2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18-3.56; p = 0.011) that was adjusted for potential confounders including β-catenin, COX-2, FASN, LINE-1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and β-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis. [ABSTRACT FROM AUTHOR]

The CpG island methylator phenotype (CIMP) with widespread promoter CpG island methylation is a phenotype in colorectal cancer, associated with microsatellite instability (MSI) and BRAF mutation. Genome-wide hypomethylation may also play an important role in genomic instability. However, the relation between global DNA methylation level and methylation in individual CpG islands remains uncertain. Utilizing 869 population-based colorectal cancers, we measured long interspersed nucleotide element-1 (LINE-1) methylation level by Pyrosequencing, which correlates with global DNA methylation level. We quantified DNA methylation in 8 CIMP-specific promoters ( CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) by real-time PCR (MethyLight technology). LINE-1 methylation levels in tumors were approximately normally distributed (mean, 61.4%; median, 62.3%; standard deviation, 9.6%). Among the 869 tumors, 128 (15%) were classified as CIMP-high (≥6/8 methylated promoters). The mean LINE-1 methylation level was higher in CIMP-high tumors (65.1%, p < 0.0001) than non-CIMP-high tumors (60.7%), and higher in MSI-high tumors (64.7%, p < 0.0001) than non-MSI-high tumors (60.7%). When tumors were stratified by MSI/CIMP status, compared to non-MSI-high non-CIMP-high tumors (mean LINE-1 methylation level, 60.4%), the mean LINE-1 methylation level was higher in MSI-high CIMP-high (64.8%, p < 0.0001), MSI-high non-CIMP-high (64.6%, p = 0.03) and non-MSI-high CIMP-high tumors (66.1%, p = 0.0003). In addition, 18q loss of heterozygosity in non-MSI-high tumors was correlated with LINE-1 hypomethylation ( p = 0.004). In conclusion, both CIMP-high and MSI-high are inversely associated with LINE-1 hypomethylation, suggesting that CIMP/MSI and genomic hypomethylation may represent different pathways to colorectal cancer. Our data also support a possible link between global hypomethylation and chromosomal instability. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]