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BackgroundInitiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC.MethodsThe authors conducted a population-based, case-control study of individuals aged 40 to 49years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied.ResultsFamily history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis.ConclusionsOf CRC cases aged 40 to 49years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

BACKGROUND Colorectal cancer (CRC) risk varies by race and sex. This study, 1 of 2 microsimulation analyses to inform the 2018 American Cancer Society CRC screening guideline, explored the influence of race and sex on optimal CRC screening strategies. METHODS Two Cancer Intervention and Surveillance Modeling Network microsimulation models, informed by US incidence data, were used to evaluate a variety of screening methods, ages to start and stop, and intervals for 4 demographic subgroups (black and white males and females) under 2 scenarios for the projected lifetime CRC risk for 40‐year‐olds: 1) assuming that risk had remained stable since the early screening era and 2) assuming that risk had increased proportionally to observed incidence trends under the age of 40 years. Model‐based screening recommendations were based on the predicted level of benefit (life‐years gained) and burden (required number of colonoscopies), the incremental burden‐to‐benefit ratio, and the relative efficiency in comparison with strategies with similar burdens. RESULTS When lifetime CRC risk was assumed to be stable over time, the models differed in the recommended age to start screening for whites (45 vs 50 years) but consistently recommended screening from the age of 45 years for blacks. When CRC risk was assumed to be increased, the models recommended starting at the age of 45 years, regardless of race and sex. Strategies recommended under both scenarios included colonoscopy every 10 or 15 years, annual fecal immunochemical testing, and computed tomographic colonography every 5 years through the age of 75 years. CONCLUSIONS Microsimulation modeling suggests that CRC screening should be considered from the age of 45 years for blacks and for whites if the lifetime risk has increased proportionally to the incidence for younger adults. Cancer 2018;124:2974‐85. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., An established modeling method suggests that screening should be considered from the age of 45 years for African American men and women, and for white men and women if their lifetime risk of colorectal cancer increases similarly to trends observed at younger ages. See also pages 2964‐73.

The CpG Island Methylator Phenotype (CIMP) is a major molecular pathway in colorectal cancer (CRC). Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1.

The biological environment varies across the colorectum and may therefore differently affect neoplastic growth in the proximal and distal colon. The aim of the study was to evaluate the risk for recurrent adenomas and their anatomic location based on adenoma location at baseline colonoscopy.

Individuals with a strong family history of colorectal cancer (CRC) have significant risk for CRC, though adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored, telephone counseling intervention can increase adherence to colonoscopy in members of high risk families in a randomized, controlled trial.

The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L).

Changes in the methylation levels of DNA from white blood cells (WBCs) are putatively associated with an elevated risk for several cancers. The aim of this study was to investigate the association between colorectal cancer (CRC) and the methylation status of three DNA repetitive elements in DNA from peripheral blood. WBC DNA from 539 CRC cases diagnosed before 60 years of age and 242 sex and age frequency-matched healthy controls from the Australasian Colorectal Cancer Family Registry were assessed for methylation across DNA repetitive elements Alu, LINE-1 and Sat2 using MethyLight. The percentage of methylated reference (PMR) of cases and controls was calculated for each marker. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression adjusted for potential confounders. CRC cases demonstrated a significantly higher median PMR for LINE-1 (p < 0.001), Sat2 (p < 0.001) and Alu repeats (p = 0.02) when compared with controls. For each of the DNA repetitive elements, individuals with PMR values in the highest quartile were significantly more likely to have CRC compared with those in the lowest quartile (LINE-1 OR = 2.34, 95%CI = 1.48–3.70; p < 0.001, Alu OR = 1.83, 95%CI = 1.17–2.86; p = 0.01, Sat2 OR = 1.72, 95%CI = 1.10–2.71; p = 0.02). When comparing the OR for the PMR of each marker across subgroups of CRC, only the Alu marker showed a significant difference in the 5-fluoruracil treated and nodal involvement subgroups (both p = 0.002). This association between increasing methylation levels of three DNA repetitive elements in WBC DNA and early-onset CRC is novel and may represent a potential epigenetic biomarker for early CRC detection.

Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations.

Colorectal cancer (CRC) is a significant cause of mortality and morbidity in the United States, much of which could be prevented through adequate screening. Consensus guidelines recommend that high-risk groups initiate screening earlier with colonoscopy and more frequently than average risk persons. However, a large proportion of high risk individuals do not receive regular colonoscopic screening. The Family Health Promotion Project (FHPP) is a randomized-controlled trial to test the effectiveness of a telephone-based counseling intervention to increase adherence to risk-appropriate colonoscopy screening in high risk individuals. Unaffected members of CRC families from two national cancer family registries were enrolled (n=632) and randomized to receive either a single session telephone counseling intervention using Motivational Interviewing techniques or a minimal mail-out intervention. The primary endpoint, rate of colonoscopy screening, was assessed at 6, 12 and 24 months post-enrollment. In this paper, we describe the research design and telephone counseling intervention of the FHPP trial, and report baseline data obtained from the two high risk cohorts recruited into this trial. Results obtained at baseline confirm the need for interventions to promote colonoscopy screening among these high risk individuals, as well as highlighting several key opportunities for intervention, including increasing knowledge about risk-appropriate screening guidelines, and providing both tailored risk information and barriers counseling.

A diet high in red meat is an established colorectal cancer (CRC) risk factor. Carcinogens generated during meat cooking have been implicated as causal agents, and can induce oxidative DNA damage, which elicits repair by the base excision repair (BER) pathway.

Suggested intervals for postpolypectomy surveillance colonoscopy are currently based on the adenoma findings from the most recent examination.To determine the risk for clinically significant adenoma recurrence on the basis of the results of 2 previous colonoscopies.Prospective cohort study.Academic and private centers in North America.Participants in an adenoma chemoprevention trial in which all participants had 1 or more adenoma found on complete colonoscopy at entry. For this analysis, only participants whose qualifying adenoma was their first were included. All participants then underwent second and third study colonoscopies at roughly 3-year intervals.Proportion of patients with high-risk findings at the third study colonoscopy--either at least 1 advanced (or = 1 cm or advanced histology) adenoma or multiple (or = 3) adenomas.Fifty-eight of 564 participants (10.3%) had high-risk findings at the third study examination. If the second examination showed high-risk findings, then results from the first examination added no significant information about the probability of high-risk findings on the third examination (18.2% for high-risk findings on the first examination vs. 20.0% for low-risk findings on the first examination; P = 0.78). If the second examination showed no adenomas, then the results from the first examination added significant information about the probability of high-risk findings on the third examination (12.3% if the first examination had high-risk findings vs. 4.9% if the first examination had low-risk findings; P = 0.015).This observational study cannot specifically examine adenoma recurrence risk at intervals suggested for patients with low-risk adenomas (for example, 5 years vs. 10 years).Information from 2 previous examinations may help identify low-risk populations that benefit little from intense surveillance. Surveillance guidelines might be tailored in selected patients to use information from 2 previous examinations, not just the most recent one.National Institutes of Health.

Background Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a decreased mortality from colorectal cancer (CRC). NSAIDs induce apoptotic cell death in colon cancer cells in vitro and inhibit growth of neoplastic colonic mucosa in vivo however, the biochemical mechanisms required for these growth inhibitory effects are not well defined. We previously reported that metabolites of the NSAID sulindac downregulate extracellular-signal regulated kinase 1/2 (ERK1/2) signaling and that this effect is both necessary and sufficient for the apoptotic effects of these drugs. The goal of this project was to specifically test the hypothesis that sulindac metabolites block activation and/or expression of the epidermal growth factor (EGF) receptor (EGFR). Methods HT29 human colon cancer cells were treated with EGF, alone, or in the presence of sulindac sulfide or sulindac sulfone. Cells lysates were assayed by immunoblotting for phosphorylated EGFR (pEGFR, pY1068), total EGFR, phosphorylated ERK1/2 (pERK1/2), total ERK1/2, activated caspase-3, and α-tubulin. Results EGF treatment rapidly induced phosphorylation of both EGFR and ERK1/2 in HT29 colon cancer cells. Pretreatment with sulindac metabolites for 24 h blocked EGF-induced phosphorylation of both EGFR and ERK1/2 and decreased total EGFR protein expression. Under basal conditions, downregulation of pEGFR and total EGFR was detected as early as 12 h following sulindac sulfide treatment and persisted through at least 48 h. Sulindac sulfone induced downregulation of pEGFR and total EGFR was detected as early as 1 h and 24 h, respectively, following drug treatment, and persisted through at least 72 h. EGFR downregulation by sulindac metabolites was observed in three different CRC cell lines, occurred prior to the observed downregulation of pERK1/2 and induction of apoptosis by these drugs, and was not dependent of caspase activation. Conclusion These results suggest that downregulation of EGFR signaling by sulindac metabolites may occur, at least in part, by inhibiting activation and expression of EGFR. Inhibition of EGFR signaling may account for part of the growth inhibitory and chemopreventive effects of these compounds.

BackgroundConstipation, a low fiber diet, sedentary lifestyle and gravidity are commonly assumed to increase the risk of hemorrhoids. However, evidence regarding these factors is limited. We examined the association between commonly cited risk factors and the prevalence of hemorrhoids.MethodsWe performed a cross sectional study of participants who underwent a colonoscopy in a colorectal adenoma prevention trial and who had a detailed assessment of bowel habits, diet and activity. The presence of hemorrhoids was extracted from the subjects’ colonoscopy reports. We used logistic regression to estimate odds ratios and 95% confidence intervals while adjusting for age and sex.ResultsThe study included 2,813 participants. Of these, 1,074 had hemorrhoids recorded. Constipation was associated with an increased prevalence of hemorrhoids (OR 1.43, 95% CI 1.11, 1.86). Of the fiber subtypes, high grain fiber intake was associated with a reduced risk (OR for quartile 4 versus quartile 1 = 0.78, 95% CI 0.62, 0.98). We found no association when comparing gravid and nulligravida women (OR 0.93, 95% CI 0.62–1.40). Sedentary behavior was associated with a reduced risk (OR 0.80, 95% CI 0.65–0.98), but not physical activity (OR 0.83, 95% CI 0.66–1.03). Neither being overweight nor obese was associated with the presence of hemorrhoids (OR 0.89, 95% CI 0.72–1.09 and OR 0.86, 95% CI 0.70–1.06).ConclusionsConstipation is associated with an increased risk of hemorrhoids. Gravidity and physical activity do not appear to be associated. High grain fiber intake and sedentary behavior are associated with a decreased risk of hemorrhoids.

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.

BackgroundCalcium supplements are widely used among older adults for osteoporosis prevention and treatment. However, their effect on creatinine levels and kidney function has not been well studied.MethodsWe investigated the effect of calcium supplementation on blood creatinine concentration in a randomized controlled trial of colorectal adenoma chemoprevention conducted between 2004–2013 at 11 clinical centers in the United States. Healthy participants (N = 1,675) aged 45–75 with a history of colorectal adenoma were assigned to daily supplementation with calcium (1200 mg, as carbonate), vitamin D3 (1000 IU), both, or placebo for three or five years. Changes in blood creatinine and total calcium concentration were measured after one year of treatment and multiple linear regression was used to estimate effects on creatinine concentrations.ResultsAfter one year of treatment, blood creatinine was 0.013±0.006 mg/dL higher on average among participants randomized to calcium compared to placebo after adjustment for other determinants of creatinine (P = 0.03). However, the effect of calcium treatment appeared to be larger among participants who consumed the most alcohol (2–6 drinks/day) or whose estimated glomerular filtration rate (eGFR) was less than 60 ml/min/1.73 m2 at baseline. The effect of calcium treatment on creatinine was only partially mediated by a concomitant increase in blood total calcium concentration and was independent of randomized vitamin D treatment. There did not appear to be further increases in creatinine after the first year of calcium treatment.ConclusionsAmong healthy adults participating in a randomized clinical trial, daily supplementation with 1200 mg of elemental calcium caused a small increase in blood creatinine. If confirmed, this finding may have implications for clinical and public health recommendations for calcium supplementation.Trial RegistrationClinicalTrials.gov NCT00153816

BackgroundRecent genome-wide studies identified a risk locus for colorectal cancer at 18q21, which maps to the SMAD7 gene. Our objective was to confirm the association between SMAD7 SNPs and colorectal cancer risk in the multi-center Colon Cancer Family Registry.Materials and Methods23 tagging SNPs in the SMAD7 gene were genotyped among 1,592 population-based and 253 clinic-based families. The SNP-colorectal cancer associations were assessed in multivariable conditional logistic regression.ResultsAmong the population-based families, both SNPs rs12953717 (odds ratio, 1.29; 95% confidence interval, 1.12–1.49), and rs11874392 (odds ratio, 0.80; 95% confidence interval, 0.70–0.92) were associated with risk of colorectal cancer. These associations were similar among the population- and the clinic-based families, though they were significant only among the former. Marginally significant differences in the SNP-colorectal cancer associations were observed by use of nonsteroidal anti-inflammatory drugs, cigarette smoking, body mass index, and history of polyps.ConclusionsSMAD7 SNPs were associated with colorectal cancer risk in the Colon Cancer Family Registry. There was evidence suggesting that the association between rs12953717 and colorectal cancer risk may be modified by factors such as smoking and use of nonsteroidal anti-inflammatory drugs.

PurposePrior studies suggest cigarette smoking is associated with 1.5- to twofold increased risk of colorectal adenomas and possibly a higher risk of serrated polyps. Further clarification of risk differences between adenomas and serrated polyps is needed with regard to co-occurrence and polyp location.Methods We conducted a combined analysis of conventional adenoma and serrated polyp occurrence using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. All participants had ≥1 adenomas removed at baseline and were followed for up to 4years. Smoking habits and other lifestyle factors were collected at baseline using questionnaires. We used generalized linear regression to estimate risk ratios and 95% confidence intervals.ResultsSmokers were at slightly increased risk of adenomas compared to never smokers [current: RR 1.29 (95% CI 1.11–1.49) and former: RR 1.18 (1.05–1.32)]. Smoking was associated with greater risk of serrated polyps [current: RR 2.01 (1.66–2.44); former: RR 1.42 (1.20–1.68)], particularly in the left colorectum. Associations between current smoking and occurrence of serrated polyps only [RR 2.33 (1.76–3.07)] and both adenomas and serrated polyps [RR 2.27 (1.68–3.06)] were more pronounced than for adenomas only [RR 1.31 (1.08–1.58)]. Results were similar for other smoking variables and did not differ by gender or for advanced adenomas.ConclusionsCigarette smoking has only a weak association with adenomas, but is associated with a significantly increased risk of serrated polyps, particularly in the left colorectum. Since a minority of left-sided serrated polyps is thought to have malignant potential, the role of smoking in initiation phases of carcinogenesis is uncertain.

Colorectal cancer (CRC) is potentially preventable. Chemoprevention, a focus of research for the past three decades, aims to prevent or delay the onset of cancer through the regression or prevention of colonic adenomas. Ideal pharmacological agents for chemoprevention should be cheap and nontoxic. Although data indicate that aspirin can reduce the risk of CRC in the general population, the highest return from chemopreventive strategies would be expected in patients with the highest risk of developing the disease, particularly those with a defined hereditary predisposition. Despite compelling data showing that a large number of chemopreventive agents show promise in preclinical CRC models, clinical studies have yielded conflicting results. This Review provides a historical and methodological perspective of chemoprevention in familial adenomatous polyposis and Lynch syndrome, and summarizes the current status of CRC chemoprevention in humans. Our goal is to critically focus on important issues of trial design, with particular attention on the choice of appropriate trial end points, how such end points should be measured, and which patients are the ideal candidates to be included in a chemopreventive trial.