Colorectal Cancer Risk Assessment Research Articles

Potential of pre-diagnostic metabolomics for colorectal cancer risk assessment or early detection

This systematic review investigates the efficacy of metabolite biomarkers for risk assessment or early detection of colorectal cancer (CRC) and its precursors, focusing on pre-diagnostic biospecimens. Searches in PubMed, Web of Science, and SCOPUS through December 2023 identified relevant prospective studies. Relevant data were extracted, and the risk of bias was assessed with the QUADAS-2 tool. Among the 26 studies included, significant heterogeneity existed for case numbers, metabolite identification, and validation approaches. Thirteen studies evaluated individual metabolites, mainly lipids, while eleven studies derived metabolite panels, and two studies did both. Nine panels were internally validated, resulting in an area under the curve (AUC) ranging from 0.69 to 0.95 for CRC precursors and 0.72 to 1.0 for CRC. External validation was limited to one panel (AUC = 0.72). Metabolite panels and lipid-based biomarkers show promise for CRC risk assessment and early detection but require standardization and extensive validation for clinical use.

Effectiveness of colonoscopy, immune fecal occult blood testing, and risk-graded screening strategies in colorectal cancer screening.

Colorectal cancer (CRC) is one of the most common malignant tumors, and early screening is crucial to improving the survival rate of patients. The combination of colonoscopy and immune fecal occult blood detection has garnered significant attention as a novel method for CRC screening. Colonoscopy and fecal occult blood tests, when combined, can improve screening accuracy and early detection rates, thereby facilitating early intervention and treatment. However, certain risks and costs accompany it, making the establishment of a risk classification model crucial for accurate classification and management of screened subjects. To evaluate the feasibility and effectiveness of colonoscopy, immune fecal occult blood test (FIT), and risk-graded screening strategies in CRC screening. Based on the randomized controlled trial of CRC screening in the population conducted by our hospital May 2020 to May 2023, participants who met the requirements were randomly assigned to a colonoscopy group, an FIT group, or a graded screening group at a ratio of 1:2:2 (after risk assessment, the high-risk group received colonoscopy, the low-risk group received an FIT test, and the FIT-positive group received colonoscopy). The three groups received CRC screening with different protocols, among which the colonoscopy group only received baseline screening, and the FIT group and the graded screening group received annual follow-up screening based on baseline screening. The primary outcome was the detection rate of advanced tumors, including CRC and advanced adenoma. The population participation rate, advanced tumor detection rate, and colonoscopy load of the three screening programs were compared. A total of 19373 subjects who met the inclusion and exclusion criteria were enrolled, including 8082 males (41.7%) and 11291 females (58.3%). The mean age was 60.05 ± 6.5 years. Among them, 3883 patients were enrolled in the colonoscopy group, 7793 in the FIT group, and 7697 in the graded screening group. Two rounds of follow-up screening were completed in the FIT group and the graded screening group. The graded screening group (89.2%) and the colonoscopy group (42.3%) had the lowest overall screening participation rates, while the FIT group had the highest (99.3%). The results of the intentional analysis showed that the detection rate of advanced tumors in the colonoscopy group was greater than that of the FIT group [2.76% vs 2.17%, odds ratio (OR) = 1.30, 95% confidence interval (CI): 1.01-1.65, P = 0.037]. There was no significant difference in the detection rate of advanced tumors between the colonoscopy group and the graded screening group (2.76% vs 2.35%, OR = 1.9, 95%CI: 0.93-1.51, P = 0.156), as well as between the graded screening group and the FIT group (2.35% vs 2.17%, OR = 1.09%, 95%CI: 0.88-1.34, P = 0.440). The number of colonoscopy examinations required for each patient with advanced tumors was used as an index to evaluate the colonoscopy load during population screening. The graded screening group had the highest colonoscopy load (15.4 times), followed by the colonoscopy group (10.2 times), and the FIT group had the lowest (7.8 times). A hierarchical screening strategy based on CRC risk assessment is feasible for screening for CRC in the population. It can be used as an effective supplement to traditional colonoscopy and FIT screening programs.

Sarcopenia is independently associated with poor preoperative physical fitness in patients undergoing colorectal cancer surgery.

Accurate preoperative risk assessment for major colorectal cancer (CRC) surgery remains challenging. Body composition (BC) and cardiopulmonary exercise testing (CPET) can be used to evaluate risk. The relationship between BC and CPET in patients undergoing curative CRC surgery is unclear. Consecutive patients undergoing CPET prior to CRC surgery between 2010 and 2020 were identified between two different UK hospitals. Body composition phenotypes such as sarcopenia, myosteatosis, and visceral obesity were defined using widely accepted thresholds using preoperative single axial slice CT image at L3 vertebrae. Relationships between clinicopathological, BC, and CPET variables were investigated using linear regression analysis. Two hundred eighteen patients with stage I-III CRC were included. The prevalence of sarcopenia, myosteatosis, and visceral obesity was 62%, 33%, and 64%, respectively. The median oxygen uptake at anaerobic threshold (VO2 at AT) was 12.2mL/kg/min (IQR 10.6-14.2), and oxygen uptake at peak exercise (VO2 peak) was 18.8mL/kg/min (IQR 15.4-23). On univariate linear regression analysis, male sex (P<0.001) was positively associated with VO2 at AT. While ASA grade (P<0.001) and BMI (P=0.007) were negatively associated with VO2 at AT, on multivariate linear regression analysis, these variables remained significant (P<0.05). On univariate linear regression analysis, male sex (P<0.001) was positively associated with VO2 peak, whereas age (P<0.001), ASA grade (P<0.001), BMI (P=0.003), sarcopenia (P=0.015), and myosteatosis (P<0.001) were negatively associated with VO2 peak. On multivariate linear regression analysis age (P<0.001), ASA grade (P<0.001), BMI (P<0.001), and sarcopenia (P=0.006) were independently and negatively associated with VO2 peak. The novel finding that sarcopenia is independently associated with reduced VO2 peak performance in CPET supports the supposition that reduced muscle mass relates to poor physical function in CRC patients. Further work should be undertaken to assess whether sarcopenia diagnosed on CT can act as suitable surrogate for CPET to further enhance personalized risk stratification.

Blood-Based Epigenetic Age Acceleration and Incident Colorectal Cancer Risk: Findings from a Population-Based Case-Control Study.

This study investigates the association between epigenetic age acceleration (EAA) derived from DNA methylation and the risk of incident colorectal cancer (CRC). We utilized data from a random population sample of 9,360 individuals (men and women, aged 45-69) from the HAPIEE Study who had been followed up for 16 years. A nested case-control design yielded 35 incident CRC cases and 354 matched controls. Six baseline epigenetic age (EA) measures (Horvath, Hannum, PhenoAge, Skin and Blood (SB), BLUP, and Elastic Net (EN)) were calculated along with their respective EAAs. After adjustment, the odds ratios (ORs) for CRC risk per decile increase in EAA ranged from 1.20 (95% CI: 1.04-1.39) to 1.44 (95% CI: 1.21-1.76) for the Horvath, Hannum, PhenoAge, and BLUP measures. Conversely, the SB and EN EAA measures showed borderline inverse associations with ORs of 0.86-0.87 (95% CI: 0.76-0.99). Tertile analysis reinforced a positive association between CRC risk and four EAA measures (Horvath, Hannum, PhenoAge, and BLUP) and a modest inverse relationship with EN EAA. Our findings from a prospective population-based-case-control study indicate a direct association between incident CRC and four markers of accelerated baseline epigenetic age. In contrast, two markers showed a negative association or no association. These results warrant further exploration in larger cohorts and may have implications for CRC risk assessment and prevention.

External validation of the colorectal cancer risk score LiFeCRC using food frequency questions in the HUNT study

PurposeTo mitigate the increasing colorectal cancer (CRC) incidence globally and prevent CRC at the individual level, individual lifestyle information needs to be easily translated into CRC risk assessment. Several CRC risk prediction models exist and their clinical usefulness depends on their ease of use. Our objectives were to assess and externally validate the LiFeCRC score in our independent, unselected population and to investigate the use of simpler food frequency measurements in the score.MethodsIncidental colon and rectal cancer cases were compared to the general population among 78,580 individuals participating in a longitudinal health study in Norway (HUNT). Vegetable, dairy product, processed meat and sugar/confectionary consumption was scored based on food frequency. The LiFeCRC risk score was calculated for each individual.ResultsOver a median of 10 years following participation in HUNT, colon cancer was diagnosed in 1355 patients and rectal cancer was diagnosed in 473 patients. The LiFeCRC score using food frequencies demonstrated good discrimination in CRC overall (AUC 0.77) and in sex-specific models (AUC men 0.76 and women 0.77) in this population also including individuals ≥ 70 years and patients with diabetes. It performed somewhat better in colon (AUC 0.80) than in rectal cancer (AUC 0.72) and worked best for female colon cancer (AUC 0.81).ConclusionReadily available clinical variables and food frequency questions in a modified LiFeCRC score can identify patients at risk of CRC and may improve primary prevention by motivating to lifestyle change or participation in the CRC screening programme.

The association of the killer cell immunoglobulin-like receptor (KIR) genotype distribution and HLA-C ligands in colorectal cancer in the eastern region of Saudi Arabia

Colorectal cancer (CRC) is the most common cause of cancer-related mortality globally. It ranks as the most common cancer among men and the third most prevalent among women in Saudi Arabia, especially in the eastern region. The immune system's response to cancer is significantly influenced by natural killer cells through their killer-cell immunoglobulin-like receptors (KIRs) interaction with human leukocyte antigen (HLA) molecules. Our research aimed to target a homogeneous ethnic group in the eastern region of Saudi Arabia, analyzing the distribution of 16 KIR genes and HLA-C1/C2 allotypes in 50 CRC patients and 63 healthy controls using the sequence-specific PCR amplification method. Findings revealed significantly lower frequencies of the 2DL2 and 3DL1 genes in CRC patients compared to controls (OR = 2.21; P = 0.04) and (OR = 7.46; P = 0.00009), respectively. Additionally, a higher prevalence of HLA-C2 was noted in CRC patients (84 %) versus controls (66.7 %) (OR = 2.26; P = 0.04). Conversely, the HLA-C1C2 combination showed a protective effect against CRC (OR = 0.38; P = 0.04). Our combinatorial analysis further identified specific gene combinations correlating with CRC risk or protection. Notably, the absence of KIR2DL2 combined with the presence of KIR2DS2 emerged as a significant risk factor, while various combinations involving KIR2DL2 and/or KIR2DS1 with HLA-C ligands were associated with either increased susceptibility or protection. The study underscores the protective role of KIR2DL2 against CRC in Saudi Arabia's eastern region and suggests that the absence of KIR2DL2, especially when KIR2DS2 is present, might increase CRC risk. This research contributes to understanding genetic influences on CRC susceptibility, emphasizing the potential of KIR and HLA interactions as biomarkers for CRC risk assessment.

Association between lifestyle and dietary preference factors and conventional adenomas and serrated polyps.

Both conventional adenoma (AD) and serrated polyp (SP) were known precursor lesions of colorectal cancer (CRC). Modifiable lifestyle factors were significantly associated with CRC risk, but whether these factors were related to the risk of different precursors of CRC needed to be clarified. This study aimed to evaluate the risks of AD and SP caused by lifestyle factors and compare the risk differences between AD and SP. The study population was from the CRC screening cohort in Hangzhou, China. A total of 458,457 eligible individuals volunteered to undergo initial screening including the fecal immunochemical test (FIT) and the CRC risk assessment. Finally, 13,993 participants who had undergone colonoscopy tests and had been diagnosed at designated hospitals were selected in this study. All participants were required to fill out a questionnaire during the initial screening for collecting their information. The generalized estimate equation (GEE) model was used to assess the association between lifestyle factors/dietary preferences and AD/SP. The body mass index (BMI) and smoking were positively associated with the risks of only SP (BMI: OR = 1.50, 95%CI: 1.23-1.84; smoking: OR = 1.29, 95%CI: 1.07-1.55), only AD (BMI: OR = 1.53, 95%CI: 1.28-1.82; OR = 1.24, 95%CI: 1.11-1.39), and synchronous SP and AD (BMI: OR = 1.97, 95%CI: 1.40-2.75; smoking: OR = 1.53, 95%CI: 1.27-1.85). In the case-group comparison, smoking was more strongly associated with the risk of synchronous SP and AD than only AD. Alcohol drinking was positively associated with the risk of AD (OR = 1.28, 95%CI: 1.14-1.44), but no statistically significant difference was observed in risks in the case-group comparison. Furthermore, whole-grain intake was associated with a decreased risk of only AD (OR = 0.78, 95%CI: 0.65-0.93). However, white meat intake was positively associated with risks of only SP when compared with AD cases (OR = 1.60, 95%CI: 1.15-2.23). The current study identified common risk factors such as BMI and smoking as well as different risks of certain factors (e.g., alcohol drinking and whole-grain intake) for SP and AD. However, there were still some factors, especially diet-related factors, that have not been fully elucidated in their association with the two lesions. Further research is needed in future to confirm and develop prevention strategies for different lesions.

Potential value of detection of minimal residual disease in colorectal cancer following radical resection.

Although there has been significant advancement in the identification and management of colorectal cancer (CRC) in recent years, there is still room for improvement in the current standard treatment regimen. One area of concern is the lack of reliable tumor markers to predict treatment efficacy and guide tailored care. Due to its dynamic, effective, and non-invasive benefits over tissue biopsy, the detection of minimal or molecular residual lesions (MRD) based on circulating tumor DNA (ctDNA) is beneficial to the clinical development of drugs for patients with CRC after radical treatment, as well as for continuous monitoring of tumor recurrence and malignancy molecular gene evolution. The detection of ctDNA can currently be used to guide individual postoperative auxiliary treatment decisions (upgrade or downgrade treatment) in CRC, stratify the risk of clinical recurrence more precisely, and predict the risk of recurrence in advance of imaging examination, according to a large number of observational or prospective clinical studies. With increasing clarity comes the possibility of selecting a regimen of treatment based on postoperative ctDNA, which also improves the accuracy of clinical recurrence risk assessment for CRC. Therefore, it is anticipated that the identification of ctDNA would alter the current framework for dealing with CRC and lead to individualized, stratified precision therapy; however, additional confirmation will require subsequent high-quality, prospective, large-scale randomized controlled studies. This article will provide an overview of the definition and clinical significance of MRD, the primary indications and technological challenges for MRD detection, along with the advancement in clinical research about ctDNA detection following radical resection of the CRC.

Abstract B145: Validation of a colorectal cancer risk prediction model in US Black women

Abstract Background: The National Cancer Institute’s Colorectal Cancer Risk Assessment Tool (NCI-CCRAT) estimates an individual's five-year risk of developing colorectal cancer. It was developed by estimating relative risks from a population of US White women and men and incorporating race, gender, and age-specific incidence data from population-based cancer registries. However, the model performance has not been assessed for Black Americans, who have the highest colorectal cancer incidence and mortality rates of any US racial/ethnic group. Methods: The NCI-CCRAT estimates the absolute risk of colorectal cancer based on an individual’s age, sex, family history of colorectal cancer, sigmoidoscopy/colonoscopy, polyps, smoking, physical activity, regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use, vegetable intake, body mass index, and hormone replacement therapy use. Validation of the NCI-CCRAT was performed using prospective data from 57,558 participants ages 40 to 84 years in the Black Women's Health Study (BWHS). We predicted 5-year absolute risk using data from 2001 through 2015 in three 5-year prediction periods: 2001-2005, 2006-2010, and 2011-2015. To assess model performance, we computed calibration by comparing the expected number of colorectal cancer cases predicted by the model to the observed number of cases (E/O) in the BWHS overall and in subgroups of the population. We assessed discriminatory accuracy by calculating the area under the curve (AUC). Results: During follow-up from 2001 through 2015 (634,512 person-years), 433 BWHS participants developed invasive colorectal cancer. Based on the NCI-CCRAT, 543 cases were expected. The NCI-CCRAT was well-calibrated in the first 5-year prediction period (2001-2005 E/O=1.03, 95% CI: 0.88–1.21), but the model overestimated risk in the subsequent 5-year prediction periods, with E/O=1.30 for 2006-2010 and E/O=1.44 for 2011-2015. The overall E/O ratio was 1.25 (95% confidence interval: 1.14–1.38), indicating that NCI-CCRAT overestimated the number of cases in this population of Black women. Of note, associations with colorectal cancer were weaker in the BWHS than in the development cohort for vigorous physical activity, aspirin/NSAID use, vegetable intake, and body mass index. We estimated discriminatory accuracy only for the first 5-year prediction period (2001-2005, N cases=151) for which the model was well calibrated, and obtained an age-adjusted AUC of 0.61 (95% CI: 0.57–0.66). Conclusions: The NCI-CCRAT overestimated the overall number of colorectal cancer cases by 25% in this prospective cohort of Black women, possibly due to population-specific differences in the relative risks of key factors driving colorectal cancer incidence. Discriminatory accuracy was similar to measures from the original validation cohort of White women and men. Impact: This study suggests that further research is needed to determine the most important predictors of colorectal cancer etiology in Black women and to develop and test a colorectal cancer risk prediction model for Black Americans. Citation Format: Jessica L. Petrick, Nelsy Castro-Webb, Gary R. Zirpoli, Kerrie P. Nelson, Julie R. Palmer, Ruth M. Pfeiffer. Validation of a colorectal cancer risk prediction model in US Black women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B145.

Transcending Boundaries: Integrating Genetic Insights for Improved Colorectal Cancer Risk Assessment in Multiethnic Populations

Colorectal cancer (CRC) remains a significant global health concern, with variations in incidence and genetic susceptibility observed among diverse ethnic populations. This article presents a groundbreaking study titled "Transcending Boundaries: Integrating Genetic Insights for Improved Colorectal Cancer Risk Assessment in Multiethnic Populations." The research aims to enhance precision medicine approaches by synthesizing genome-wide association studies (GWAS) data from various ancestral backgrounds to improve CRC risk prediction.&#x0D; The study employs a comprehensive meta-analysis methodology, consolidating genetic data from Asian and European populations. By transcending traditional ethnic boundaries, the research seeks to identify shared and unique genetic markers associated with CRC risk across diverse groups. This integrative approach not only facilitates a more nuanced understanding of the genetic architecture of CRC but also allows for the development of a unified risk assessment model applicable to multiethnic populations.&#x0D; The findings underscore the importance of considering genetic diversity in CRC risk prediction. The integrated model demonstrates superior accuracy compared to conventional approaches, showcasing its potential for more effective and inclusive screening strategies. Moreover, the study sheds light on the need for personalized screening protocols that account for the genetic heterogeneity present in multiethnic societies.&#x0D; This research represents a significant step toward advancing the field of genetic epidemiology and precision medicine, emphasizing the importance of collaborative efforts to address health disparities across populations. The insights gained from this study hold promise for informing public health initiatives, guiding clinicians in risk assessment, and ultimately improving preventive strategies for colorectal cancer on a global scale.

Colorectal Cancer Risk Assessment and Precision Approaches to Screening: Brave New World or Worlds Apart?

Current colorectal cancer (CRC) screening recommendations take a "one-size-fits-all" approach using age as the major criterion to initiate screening. Precision screening that incorporates factors beyond age to risk stratify individuals could improve on current approaches and optimally use available resources with benefits for patients, providers, and health care systems. Prediction models could identify high-risk groups who would benefit from more intensive screening, while low-risk groups could be recommended less intensive screening incorporating noninvasive screening modalities. In addition to age, prediction models incorporate well-established risk factors such as genetics (eg, family CRC history, germline, and polygenic risk scores), lifestyle (eg, smoking, alcohol, diet, and physical inactivity), sex, and race and ethnicity among others. Although several risk prediction models have been validated, few have been systematically studied for risk-adapted population CRC screening. In order to envisage clinical implementation of precision screening in the future, it will be critical to develop reliable and accurate prediction models that apply to all individuals in a population; prospectively study risk-adapted CRC screening on the population level; garner acceptance from patients and providers; and assess feasibility, resources, cost, and cost-effectiveness of these new paradigms. This review evaluates the current state of risk prediction modeling and provides a roadmap for future implementation of precision CRC screening.

Internet-based assessment tools for predicting colorectal cancer risk: How do they communicate individualized risk to the young adult?

72 Background: Online prediction tools for cancer risk can inform individuals about their risk and potentially encourage adoption of risk-modifying health behavior. The Colorectal Cancer Risk Assessment Tool (CCRAT) is an interactive tool developed by the National Cancer Institute for estimating colorectal cancer (CRC) risk for individuals between the ages of 45 and 85 without high risk predisposing conditions. Given the rising incidence of CRC among young adults under age 50, we aimed to investigate the performance of CCRAT in estimating their CRC risk. Methods: An institutional protocol prospectively enrolled 563 patients newly diagnosed with non-hereditary CRC and administered a health behavior questionnaire at baseline. Self-reported demographics, diet and physical activity, medication use, and family history were extracted and entered into the CCRAT ( https://ccrisktool.cancer.gov/calculator.html ) to calculate their predicted 5-year and lifetime CRC risks. Health behaviors and the predicted CRC risks in reference to the population average were compared among three groups: youngest- (aged 18-44, N = 276, 49%), young- (aged 45-50, N = 178, 32%), and older-onset (aged &gt; 50, N = 109; 19%). Results: The patient groups did not significantly differ in gender or in family history of CRC, but the youngest group had significantly more non-White patients (27, 22, vs. 19%; p = 0.008) and distal tumors (80, 76 and 65%; p = 0.05). The youngest and young groups had a higher prevalence of morbid obesity (18 and 15% vs. 12%; p = 0.002) and active smokers (6 and 8% vs. 3%; p = 0.005). There were no significant differences in vegetable intake, moderate exercise, NSAID use, or female hormone use. The 5-year CRC risk was correctly predicted as “higher than average population” for a significantly smaller proportion of the youngest (42%) and young (45%) patients, when compared to their older counterpart (71%; p &lt; 0.001). Similarly, the tool communicated “higher than average” lifetime risk for CRC in only 56 and 60% of the youngest and young patients, but 72% of the older ones (p = 0.021). Conclusions: The existing risk prediction tool inadequately communicated CRC risk for adults younger than 50 years of age. Risk factors underlying young-onset CRC likely differ from and extend beyond those as currently assessed. New tools capturing age-specific risk factors are needed to accurately communicate individualized risk and potentially motivate risk-modifying lifestyles.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations

BackgroundThe genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations.MethodsA large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle.ResultsIn the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk.ConclusionsIn summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

The Colorectal cancer RISk Prediction (CRISP) trial: a randomised controlled trial of a decision support tool for risk-stratified colorectal cancer screening.

A risk-stratified approach to colorectal cancer (CRC) screening could result in a more acceptable balance of benefits and harms, and be more cost-effective. To determine the effect of a consultation in general practice using a computerised risk assessment and decision support tool (Colorectal cancer RISk Prediction, CRISP) on risk-appropriate CRC screening. Randomised controlled trial in 10 general practices in Melbourne, Australia, from May 2017 to May 2018. Participants were recruited from a consecutive sample of patients aged 50-74 years attending their GP. Intervention consultations included CRC risk assessment using the CRISP tool and discussion of CRC screening recommendations. Control group consultations focused on lifestyle CRC risk factors. The primary outcome was risk-appropriate CRC screening at 12 months. A total of 734 participants (65.1% of eligible patients) were randomised (369 intervention, 365 control); the primary outcome was determined for 722 (362 intervention, 360 control). There was a 6.5% absolute increase (95% confidence interval [CI] = -0.28 to 13.2) in risk-appropriate screening in the intervention compared with the control group (71.5% versus 65.0%; odds ratio [OR] 1.36, 95% CI = 0.99 to 1.86, P = 0.057). In those due CRC screening during follow-up, there was a 20.3% (95% CI = 10.3 to 30.4) increase (intervention 59.8% versus control 38.9%; OR 2.31, 95% CI = 1.51 to 3.53, P<0.001) principally by increasing faecal occult blood testing in those at average risk. A risk assessment and decision support tool increases risk-appropriate CRC screening in those due screening. The CRISP intervention could commence in people in their fifth decade to ensure people start CRC screening at the optimal age with the most cost-effective test.

Validation of a diagnostic prediction tool for colorectal cancer: a case-control replication study.

Early detection of colorectal cancer (CRC) is crucial for survival. Primary care, the first point of contact in most cases, needs supportive risk assessment tools. We aimed to replicate the Swedish Colorectal Cancer Risk Assessment Tool (SCCRAT) for non-metastatic CRC in primary care and examine if risk factor patterns depend on sex and age. 2,920 adults diagnosed with non-metastatic CRC during the years 2015-2019 after having visited a general practitioner the year before the diagnosis were selected from the Swedish Cancer Register and matched with 11,628 controls, using the same inclusion criteria except for the CRC diagnosis. Diagnostic codes from primary care consultations were collected from a regional health care database. Positive predictive values (PPVs) were estimated for the same 5 symptoms and combinations thereof as in the baseline study. The results for patients aged ≥50 years old in the present study were consistent with the results of the SCCRAT study. All symptoms and combinations thereof with a PPV >5% in the present study had a PPV >5% in the baseline study. The combination of bleeding with abdominal pain (PPV 9.9%) and bleeding with change in bowel habit (PPV 7.8%) were the highest observed PPVs in both studies. Similar risk patterns were seen for all ages and when men and women were studied separately. This external validation of the SCCRAT for non-metastatic CRC in primary care replicated the baseline study successfully and identified patients at high risk for CRC.

Abstract IA018: Microbiome and intestinal barriers in colon cancer

Abstract Multiple factors (e.g., risk genes, environmental triggers, immunity, and microbiome) contribute to the pathogenesis of colorectal cancer (CRC). The intestinal dysbiosis and disruption of barrier function are common manifestations of CRC. Vitamin D/Vitamin D receptor (VDR) is known to protects against dysbiosis and tumorigenesis. Considering the multiple functional roles of VDR in the development of cancer, it is important to dissect the mechanisms by which host factors contribute to the intestinal barrier function in protecting cells from tumorigenesis. Here, we reported that in human tissue, reduced VDR in the colon of CRC patients is associated with the reduced intestinal barrier and enhanced bacterial translocation to tumors. VDR deficiency in the intestinal epithelial cells led to the reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells. VDR was a transcriptional factor regulating the genes of some tight junction (TJ) Claudins. The positively correlated status of VDR and Claudins (e.g., Claudin- 5 and10) contribute to the altered intestinal permeability in tumorigenesis. In the intestinal epithelial VDR conditionally knockout VDR∆IEC mice and myeloid VDR deletion mice, dysbiosis and inflammatory cytokines in the VDR deficient context further altered TJ proteins and manipulated the barrier functions in the development of colon cancer. Furthermore, we found that mice with colonic adenomatous polyposis coli (APC) mutation reduced thickness of mucus layer and enhanced penetration of microbiota into the epithelial cells, thus enhancing tumorigenesis in the colon. Studies on host factor regulation of microbiome and barriers could be potentially applied to risk assessment, early detection, and prevention of colon cancer. These studies will provide an additional avenue to restore microbiome and barrier functions for risk assessment and prevention of CRC and other cancers. Citation Format: Jun Sun, Jilei Zhang, Yinglin Xia, Yong-Guo Zhang. Microbiome and intestinal barriers in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA018.

Meta-analysis of fecal viromes demonstrates high diagnostic potential of the gut viral signatures for colorectal cancer and adenoma risk assessment

IntroductionViruses have been reported as inducers of tumorigenesis. Little studies have explored the impact of the gut virome on the progression of colorectal cancer. However, there is still a problem with the repeatability of viral signatures across multiple cohorts. ObjectivesThe present study aimed to reveal the repeatable gut vial signatures of colorectal cancer and adenoma patients and decipher the potential of viral markers in disease risk assessment for diagnosis. Methods1,282 available fecal metagenomes from 9 published studies for colorectal cancer and adenoma were collected. A gut viral catalog was constructed via a reference-independent approach. Viral signatures were identified by cross-cohort meta-analysis and used to build predictive models based on machine learning algorithms. New fecal samples were collected to validate the generalization of predictive models. ResultsThe gut viral composition of colorectal cancer patients was drastically altered compared with healthy, as evidenced by changes in some Siphoviridae and Myoviridae viruses and enrichment of Microviridae, whereas the virome variation in adenoma patients was relatively low. Cross-cohort meta-analysis identified 405 differential viruses for colorectal cancer, including several phages of Porphyromonas, Fusobacterium, and Hungatella that were enriched in patients and some control-enriched Ruminococcaceae phages. In 9 discovery cohorts, the optimal risk assessment model obtained an average cross-cohort area under the curve of 0.830 for discriminating colorectal cancer patients from controls. This model also showed consistently high accuracy in 2 independent validation cohorts (optimal area under the curve, 0.906). Gut virome analysis of adenoma patients identified 88 differential viruses and achieved an optimal area under the curve of 0.772 for discriminating patients from controls. ConclusionOur findings demonstrate the gut virome characteristics in colorectal cancer and adenoma and highlight gut virus-bacterial synergy in the progression of colorectal cancer. The gut viral signatures may be new targets for colorectal cancer treatment. In addition, high repeatability and predictive power of the prediction models suggest the potential of gut viral biomarkers in non-invasive diagnostic tests of colorectal cancer and adenoma.

Dietary Efficacy Evaluation by Applying a Prediction Model Using Clinical Fecal Microbiome Data of Colorectal Disease to a Controlled Animal Model from an Obesity Perspective.

Obesity associated with a Western diet such as a high-fat diet (HFD) is a known risk factor for inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this study, we aimed to develop fecal microbiome data-based deep learning algorithms for the risk assessment of colorectal diseases. The effects of a HFD and a candidate food (Nypa fruticans, NF) on IBD and CRC risk reduction were also evaluated. Fecal microbiome data were obtained from 109 IBD patients, 111 CRC patients, and 395 healthy control (HC) subjects by 16S rDNA amplicon sequencing. IBD and CRC risk assessment prediction models were then constructed by deep learning algorithms. Dietary effects were evaluated based on fecal microbiome data from rats fed on a regular chow diet (RCD), HFD, and HFD plus ethanol extracts or water extracts of NF. There were significant differences in taxa when IBD and CRC were compared with HC. The diagnostic performance (area under curve, AUC) of the deep learning algorithm was 0.84 for IBD and 0.80 for CRC prediction. Based on the rat fecal microbiome data, IBD and CRC risks were increased in HFD-fed rats versus RCD-fed rats. Interestingly, in the HFD-induced obesity model, the IBD and CRC risk scores were significantly lowered by the administration of ethanol extracts of NF, but not by the administration of water extracts of NF. In conclusion, changes in the fecal microbiome of obesity by Western diet could be important risk factors for the development of IBD and CRC. The risk prediction model developed in this study could be used to evaluate dietary efficacy.

Using Online Colorectal Cancer Risk Calculators to Guide Screening Decision-Making

BackgroundSeveral online calculators estimate colorectal cancer risk, but their consistency is unknown. Our objectives were to quantify the variation in predicted risk and to determine which calculators are best used in the clinical setting. MethodsWe used the Google search engine to identify online colorectal cancer risk calculators and assessed the output of each for 3 hypothetical screening scenarios (low-, average-, and high-risk), varied by age (50, 62, 75 years), sex, and race (Black, White), with risk levels based on risk-appropriate values for variables in each model. Estimated risks for models within a given scenario were rated as consistent or inconsistent based on comparison with either the absolute magnitude of difference or average lifetime risk of colorectal cancer. Summary statistics for consistent and inconsistent estimates were compared using chi-square and Fisher's exact tests. ResultsWe identified 5 online colorectal cancer risk calculators. Inconsistencies were found in none of 5-year, 19% of 10-year, and 81% of lifetime colorectal cancer risk estimate comparisons (P < .001). For a 50-year-old, 22% of risk estimate comparisons were inconsistent, vs 33% for a 62-year-old, and 36% for a 75-year-old (P = 0.14). ConclusionsOnline colorectal cancer risk models are more consistent in predicting colorectal cancer risk for 5- and 10-year time frames compared with lifetime. For a US population, the National Cancer Institute's Colorectal Cancer Risk Assessment Tool is a rigorously developed calculator that can be used in the clinical setting to provide 5-year and lifetime risk estimates.

Fecal Microbiome Associated with Both Colon Adenomas and Lifetime Colorectal Cancer Risk.

Increasing data indicates the gut flora including bacteria and fungi combined with environmental factors are important in the pathogenesis of colorectal cancer (CRC). Understanding differences in the microbiome in patients with colon neoplasia will foster the development of biomarkers for early detection. Determine the association of microbiome with presence of adenomas and predicted CRC risk. In subjects referred for colonoscopy, the NCI CRC risk assessment tool was completed and stool for microbiome analysis as well as fecal immunochemical test (FIT) were collected. We calculated the microbiome alpha diversity using the Shannon index as well as individual bacterial and fungal species. Among 34 patients, we identified 10 with one or more adenomas. Only 2 patients were FIT positive. The median predicted lifetime CRC risk was 2.75% and the prevalence of adenoma was higher in the fourth quartile (P < 0.001). The measured alpha diversity was somewhat higher in patients with adenomas (P = 0.07). We identified 4 bacterial species with an increased relative abundance among patients with adenomas [P < 0.5]. Lifetime CRC risk was associated with 2 specific bacterial species, P. distasonis & E. hermannii [P = 0.05 & 0.09, respectively]. No associations were seen with fungal species and adenoma prevalence or lifetime CRC risk. In addition to a strong correlation of predicted CRC risk and adenoma prevalence, we also found important differences in specific bacterial species and both adenoma prevalence and CRC risk. Larger trials are needed to potentially implement further data in the clinical setting.