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Background: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance., Methods: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group)., Results: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity., Conclusions: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort., Impact: The proposed model has potential utility in risk-stratified colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Background: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants., Methods: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve., Results: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores., Conclusions: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC., Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants., Results: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10 -5 ). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings., Conclusions: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: Colonoscopy is important for colorectal cancer (CRC) screening in individuals with a positive faecal occult blood test (FOBT). The purpose of the present study was to identify factors affecting the colonoscopy screening behaviour of FOBT-positive individuals, based on the health belief model (HBM)., Methods: This study involved a cross-sectional survey of 213 individuals aged 50 years or older who underwent CRC screening at a general hospital in Seoul, Korea, as part of the Korean National Cancer Screening Programme and who tested positive on FOBT. The questionnaire was created based on HBM instruments. The collected data were analysed using descriptive statistics, and factors associated with adherence to colonoscopy were examined using logistic regression analysis., Results: Of the FOBT-positive individuals, 44.1% adhered to colonoscopy. Three of the six evaluated HBM-driven factors (perceived seriousness, perceived barriers and health motivation) significantly differed between colonoscopy-adherent and non-adherent subjects. Perceived seriousness and perceived barriers were the most important factors influencing colonoscopy screening behaviour., Conclusion: For early detection and prevention of CRC, colonoscopy screening behaviour should improve among FOBT-positive individuals. To this aim, education on the graveness of CRC should be provided, and barriers to CRC screening should be addressed., (© 2019 John Wiley & Sons Ltd.)

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10 -8 , bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Background & Aims: Guidelines for initiating colorectal cancer (CRC) screening are based on family history but do not consider lifestyle, environmental, or genetic risk factors. We developed models to determine risk of CRC, based on lifestyle and environmental factors and genetic variants, and to identify an optimal age to begin screening., Methods: We collected data from 9748 CRC cases and 10,590 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colorectal Transdisciplinary study, from 1992 through 2005. Half of the participants were used to develop the risk determination model and the other half were used to evaluate the discriminatory accuracy (validation set). Models of CRC risk were created based on family history, 19 lifestyle and environmental factors (E-score), and 63 CRC-associated single-nucleotide polymorphisms identified in genome-wide association studies (G-score). We evaluated the discriminatory accuracy of the models by calculating area under the receiver operating characteristic curve values, adjusting for study, age, and endoscopy history for the validation set. We used the models to project the 10-year absolute risk of CRC for a given risk profile and recommend ages to begin screening in comparison to CRC risk for an average individual at 50 years of age, using external population incidence rates for non-Hispanic whites from the Surveillance, Epidemiology, and End Results program registry., Results: In our models, E-score and G-score each determined risk of CRC with greater accuracy than family history. A model that combined both scores and family history estimated CRC risk with an area under the receiver operating characteristic curve value of 0.63 (95% confidence interval, 0.62-0.64) for men and 0.62 (95% confidence interval, 0.61-0.63) for women; area under the receiver operating characteristic curve values based on only family history ranged from 0.53 to 0.54 and those based only E-score or G-score ranged from 0.59 to 0.60. Although screening is recommended to begin at age 50 years for individuals with no family history of CRC, starting ages calculated based on combined E-score and G-score differed by 12 years for men and 14 for women, for individuals with the highest vs the lowest 10% of risk., Conclusions: We used data from 2 large international consortia to develop CRC risk calculation models that included genetic and environmental factors along with family history. These determine risk of CRC and starting ages for screening with greater accuracy than the family history only model, which is based on the current screening guideline. These scoring systems might serve as a first step toward developing individualized CRC prevention strategies., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk., Competing Interests: The authors have declared that no competing interests exist.

Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).

Purpose: Screening colonoscopy and flexible sigmoidoscopy (FSG) reduce the risk of colorectal cancer (CRC), but the magnitude and duration of protection, particularly against right-sided cancer, remain uncertain. We computed the incremental benefit of colonoscopy over FSG using a validated mathematical model, which reflects colorectal neoplasia growth characteristics while allowing uncertainty in endoscopic detection and removal of adenomas., Methods: We calibrated models of CRC incidence within a multistage clonal expansion framework to data from: (1) San Francisco-Oakland SEER registry (reference population) and (2) FSG long-term follow-up data from 50,757 individuals after a negative FSG in the Kaiser Permanente system. We compared the residual CRC risks after FSG with full-length colonoscopy., Results: Our model mirrors trial data with 10-year CRC risk reductions after FSG screening at age 50 years of approximately one-third; the optimal age for a 'once-only' FSG exam was between ages 50 and 60 years; and the greater benefit was for men compared with women. There were considerable incremental gains in reduction in CRC risk by colonoscopy compared with FSG with the greatest benefit for screening colonoscopy at age 50 years. These results held up against lowering the right-sided adenoma detection sensitivity by 30%, as well as reducing the curative efficacy of polypectomy throughout the colon., Conclusions: Mathematical modeling of CRC screening, which takes account of important aspects of tumor biology, demonstrates superior risk reductions by colonoscopy over FSG. Our predictions provide further rationale for recommending screening colonoscopy in average-risk populations before the age of 60.

Background & Aims: Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci., Methods: By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States., Results: We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women., Conclusions: By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The impact of physical activity on survival outcomes in patients with recurrent colon cancer has not been studied. We tested the association between the level of postdiagnosis physical activity and survival outcomes of patients with recurrent colon cancer., Patients and Methods: We conducted a prospective observational study of 237 patients with stage III colon cancer who had recurrence of disease. Physical activity was measured approximately 6 months after the completion of therapy (14 months after surgical resection) but before detection of recurrent disease. The primary end point of the study was survival time after recurrence., Results: The hazard ratio comparing patients who reported at least 18 metabolic equivalent task (MET) hours per week of physical activity with those engaging in < 3 MET hours per week was 0.71 (95% confidence interval, 0.46-1.11). Increasing total MET hours of physical activity per week was associated with a borderline statistical significance trend for improved survival after recurrence (P = .052). The benefit of physical activity on survival was not significantly modified by sex, body mass index (BMI), number of positive lymph nodes, age, baseline performance status, adjuvant chemotherapy regimen, or recurrence-free survival period., Conclusion: To our knowledge, this is the first study investigating the association of physical activity with survival outcome of patients with recurrent colon cancer. Although the association exceeded our predefined P trend < .05 for statistical significance, these findings warrant further studies of physical activity in patients with recurrent colorectal cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) is believed to arise from mutant stem cells in colonic crypts that undergo a well-characterized progression involving benign adenoma, the precursor to invasive carcinoma. Although a number of (epi)genetic events have been identified as drivers of this process, little is known about the dynamics involved in the stage-wise progression from the first appearance of an adenoma to its ultimate conversion to malignant cancer. By the time adenomas become endoscopically detectable (i.e., are in the range of 1-2 mm in diameter), adenomas are already comprised of hundreds of thousands of cells and may have been in existence for several years if not decades. Thus, a large fraction of adenomas may actually remain undetected during endoscopic screening and, at least in principle, could give rise to cancer before they are detected. It is therefore of importance to establish what fraction of adenomas is detectable, both as a function of when the colon is screened for neoplasia and as a function of the achievable detection limit. To this end, we have derived mathematical expressions for the detectable adenoma number and size distributions based on a recently developed stochastic model of CRC. Our results and illustrations using these expressions suggest (1) that screening efficacy is critically dependent on the detection threshold and implicit knowledge of the relevant stem cell fraction in adenomas, (2) that a large fraction of non-extinct adenomas remains likely undetected assuming plausible detection thresholds and cell division rates, and (3), under a realistic description of adenoma initiation, growth and progression to CRC, the empirical prevalence of adenomas is likely inflated with lesions that are not on the pathway to cancer.

Human colorectal cancer antigen GA733-2 fused to the immunoglobin Fc fragment (GA733-2-Fc) was expressed in stably transformed Drosophila melanogaster S2 cells, and the immunogenicity of recombinant GA733-2-Fc was investigated in mice. Recombinant GA733-2-Fc was secreted into a culture medium with a molecular mass of approximately 65 kDa. Recombinant GA733-2-Fc was purified to homogeneity using affinity fractionation with Protein A sepharose 4 Fast Flow. Recombinant GA733-2-Fc proteins elicited production of specific antibodies against recombinant GA733-2 by immunization through an intraperitoneal route. Recombinant GA733-2-Fc-induced antibodies showed a binding activity to human colorectal carcinoma HCT-116 cells. Secretory recombinant GA733-2-Fc from Drosophila S2 cell systems can be used as an effective experimental antigen for research in cancer vaccine development.

Several lines of evidence support the premise that screening colonoscopy reduces colorectal cancer (CRC) incidence, but there may be differential benefits for right- and left-sided tumors. To better understand the biological basis of this differential effect, we derived biomathematical models of CRC incidence trends in U.S. and U.K. populations, representing relatively high- and low-prevalence screening, respectively. Using the Surveillance Epidemiology and End Results (SEER) and the Office for National Statistics (ONS) registries (both 1973-2006), we derived stochastic multistage clonal expansion (MSCE) models for right-sided (proximal colon) and left-sided (distal colon and rectal) tumors. The MSCE concept is based on the initiation-promotion-progression paradigm of carcinogenesis and provides a quantitative description of natural tumor development from the initiation of an adenoma (via biallelic tumor suppressor gene inactivation) to the clinical detection of CRC. From 1,228,036 (SEER: 340,582; ONS: 887,454) cases, parameter estimates for models adjusted for calendar-year and birth-cohort effects showed that adenoma initiation rates were higher for right-sided tumors, whereas, paradoxically, adenoma growth rates were higher for left-sided tumors. The net effect was a higher cancer risk in the right colon only after age 70 years. Consistent with this finding, simulations of adenoma development predicted that the relative prevalence for right- versus left-sided tumors increases with increasing age, a differential effect most striking in women. Using a realistic biomathematical description of CRC development for two nationally representative registries, we show age- and sex-dependent biological gradients for right- and left-sided colorectal tumors. These findings argue for an age-, sex-, and site-directed approach to CRC screening., (Copyright 2010 AACR.)

We derive mathematical expressions for the size distribution of screen-detectable pre-malignant lesions, both conditional and unconditional on no prior detection of cancer in the tissue of interest, based on a general multistage clonal expansion model of carcinogenesis. We apply these expressions to simulate the natural history of colorectal cancer and to evaluate the effect of a screen for adenomatous polyps and concomitant intervention on cancer risk. Our approach allows the efficient simulation of multiple screens and interventions and determination of the optimal timing of the screens. We further demonstrate the utility of our approach by computing the benefits of up to two colonoscopies on the lifetime risk of colorectal cancer.