Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors

doi:10.1053/j.gastro.2018.02.021

Gastroenterology

Volume 154, Issue 8, June 2018, Pages 2152-2164.e19

https://doi.org/10.1053/j.gastro.2018.02.021 Get rights and content

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.

Graphical abstract

Section snippets

Materials and Methods

Data from 2 large consortia (9748 CRC cases and 10,590 controls): the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colorectal Transdisciplinary Study were randomly split into 2 equal halves, with half for building risk prediction models and the other for evaluating the models. The data consists of 6 case–control studies and 8 cohort-based nested case–control studies. A description of study design and characteristics of each study populations is provided in the Supplementary

Results

For both men and women, as expected, cases had significantly higher E-scores (men: mean = 59.9 [SD 28.5]; women: mean = 59.9 [SD 27.9] than controls (men: mean = 49.6 [SD 29.1]; women: mean = 49.5 [SD 29.0], with P value <10^–15. Similarly, cases had significantly higher G-scores (men: mean = 58.7 [SD 28.4]; women: mean = 58.2 [SD 28.2] than controls (men: 48.9 [SD 29.2]; women: mean = 50.0 [SD 28.6]; with P < 10^–15. Compared with controls, cases were also more likely to have a positive family

Discussion

We built sex-specific risk prediction models by including an E-score based on 19 lifestyle and environmental CRC risk factors and a G-score based on 63 common GWAS variants associated with CRC risk. Our analyses show that both scores are independent risk predictors for CRC and yield similar AUC estimates. Incorporating both scores significantly improves the discriminatory accuracy compared with using only family history, which is the current basis for US screening guidelines for CRC. It is

Acknowledgments

Part of this study was presented as an oral presentation at 2016 American Association for Cancer Research meeting in Florida. Author contributions: Conceived and designed the experiments: JJ, MD, RS, MH, PN, SB, PC, AC, JCC, GG, JG, TH, EJ, LL, LM, JP, RM, DB, JH, GR, MS, DT, MW, RP, SG, YZ, HB, RH, EW, UP, LH. Collected phenotype data and biological samples and contributed these as investigators for their respective study: MH, PN, SB, PC, AC, JCC, GG, LL, LM, DB, GR, MS, MW, HB. Analyzed and

References (50)

L. Hsu et al.
A model to determine colorectal cancer risk using common genetic susceptibility loci
Gastroenterology
(2015)
C. Zeng et al.
Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk
Gastroenterology
(2016)
U. Peters et al.
Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis
Gastroenterology
(2013)
A. Hartzler et al.
Stakeholder engagement: a key component of integrating genomic information into electronic health records
Genet Med
(2013)
D.P. Taylor et al.
Population-based family history-specific risks for colorectal cancer: a constellation approach
Gastroenterology
(2010)
Z. Wei et al.
Large sample size, wide variant spectrum, and advanced machine-learning technique boost risk prediction for inflammatory bowel disease
Am J Hum Genet
(2013)
American Cancer Society
Colorectal Cancer Facts & Figures 2014-2016
(2014)
US Preventive Services Task Force et al.
Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement
JAMA
(2016)
US Preventive Services Task Force. Final Recommendation Statement: Colorectal Cancer: Screening, Available at:...
National Center for Health Statistics. Table 72 (page 1 of 2). Use of colorectal tests or procedures among adults aged...

J.M. Inadomi

Screening for colorectal neoplasia

N Engl J Med

(2017)

A.N. Kho et al.

Electronic medical records for genetic research: results of the eMERGE consortium

Sci Transl Med

(2011)

C.G. Chute et al.

Genomic medicine, health information technology, and patient care

JAMA

(2013)

S. Ramsey et al.

Will knowledge of gene-based colorectal cancer disease risk influence quality of life and screening behavior? Findings from a population-based study

Public Health Genomics

(2010)

C.W. Drescher et al.

The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: results from a randomized controlled trial

Cancer

(2016)

D. Lieberman et al.

Screening for colorectal cancer and evolving issues for physicians and patients: a review

JAMA

(2016)

A.K. Win et al.

Risk prediction models for colorectal cancer: a review

Cancer Epidemiol Biomarkers Prev

(2012)

M.G. Dunlop et al.

Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals

Gut

(2013)

J.A. Usher-Smith et al.

Risk prediction models for colorectal cancer: a systematic review

Cancer Prev Res

(2016)

J. Jeon et al.

Incremental benefits of screening colonoscopy over sigmoidoscopy in average-risk populations: a model-driven analysis

Cancer Causes Control

(2015)

A.B. Knudsen et al.

Estimation of benefits, burden, and harms of colorectal cancer screening strategies: modeling study for the US Preventive Services Task Force

JAMA

(2016)

G. Ibáñez -Sanz et al.

Risk model for colorectal cancer in Spanish population using environmental and genetic factors: results from the MCC-Spain study

Sci Rep

(2017)

B. Murchie et al.

A new scoring system to predict the risk for high-risk adenoma and comparison of existing risk calculators

J Clin Gastroenterol

(2017)

Y. Cao et al.

Assessing individual risk for high-risk colorectal adenoma at first-time screening colonoscopy

Int J Cancer

(2015)

K.G. Yeoh et al.

The Asia-Pacific Colorectal Screening score: a validated tool that stratifies risk for colorectal advanced neoplasia in asymptomatic Asian subjects

Gut

(2011)

Cited by (224)

Colon Polyp Surveillance: Separating the Wheat From the Chaff
2024, Gastroenterology
One goal of colorectal cancer (CRC) screening is to prevent CRC incidence by removing precancerous colonic polyps, which are detected in up to 50% of screening examinations. Yet, the lifetime risk of CRC is 3.9%–4.3%, so it is clear that most of these individuals with polyps would not develop CRC in their lifetime. It is, therefore, a challenge to determine which individuals with polyps will benefit from follow-up, and at what intervals. There is some evidence that individuals with advanced polyps, based on size and histology, benefit from intensive surveillance. However, a large proportion of individuals will have small polyps without advanced histologic features (ie, “nonadvanced”), where the benefits of surveillance are uncertain and controversial. Demand for surveillance will further increase as more polyps are detected due to increased screening uptake, recent United States recommendations to expand screening to younger individuals, and emergence of polyp detection technology. We review the current understanding and clinical implications of the natural history, biology, and outcomes associated with various categories of colon polyps based on size, histology, and number. Our aims are to highlight key knowledge gaps, specifically focusing on certain categories of polyps that may not be associated with future CRC risk, and to provide insights to inform research priorities and potential management strategies. Optimization of CRC prevention programs based on updated knowledge about the future risks associated with various colon polyps is essential to ensure cost-effective screening and surveillance, wise use of resources, and inform efforts to personalize recommendations.
Colorectal Cancer Polygenic Risk Score Is Associated With Screening Colonoscopy Findings but Not Follow-Up Outcomes
2024, Gastro Hep Advances
Colorectal cancer (CRC) polygenic risk scores (PRS) may help personalize CRC prevention strategies. We investigated whether an existing PRS was associated with advanced neoplasia (AN) in a population undergoing screening and follow-up colonoscopy.
We evaluated 10-year outcomes in the Cooperative Studies Program #380 screening colonoscopy cohort, which includes a biorepository of selected individuals with baseline AN (defined as CRC or adenoma ≥10 mm or villous histology, or high-grade dysplasia) and matched individuals without AN. A PRS was constructed from 136 prespecified CRC-risk single nucleotide polymorphisms. Multivariate logistic regression was used to evaluate the PRS for associations with AN prevalence at baseline screening colonoscopy or incident AN in participants with at least one follow-up colonoscopy.
The PRS was associated with AN risk at baseline screening colonoscopy (P = .004). Participants in the lowest PRS quintile had more than a 70% decreased risk of AN at baseline (odds ratio 0.29, 95% confidence interval 0.14–0.58; P < .001) compared to participants with a PRS in the middle quintile. Using a PRS cut-off of more than the first quintile to indicate need for colonoscopy as primary screening, the sensitivity for detecting AN at baseline is 91.8%. We did not observe a relationship between the PRS and incident AN during follow-up (P = .28).
A PRS could identify individuals at low risk for prevalent AN. Ongoing work will determine whether this PRS can identify a subset of individuals at sufficiently low risk who could safely delay or be reassured about noninvasive screening. Otherwise, more research is needed to augment these genetic tools to predict incident AN during long-term follow-up.
Colorectal Cancer Risk Prediction to Tailor Screening: Will We Embrace It or KISS It Goodbye?
2023, Clinical Gastroenterology and Hepatology
Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data
2023, Clinical Gastroenterology and Hepatology
Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death.
Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40–60 years), end age (70–85 years), and screening interval (5–15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45–75, every 10 years). Key assumptions were varied in sensitivity analyses.
Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test.
Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.
Genome-wide interaction analysis of folate for colorectal cancer risk
2023, American Journal of Clinical Nutrition
Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC.
Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.
We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).
Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10^-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10^-8). No interactions were observed for dietary and total folate.
Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
Surveillance after colorectal polyp resection
2023, Best Practice and Research: Clinical Gastroenterology
Post-polypectomy surveillance has proven to reduce colorectal cancer (CRC) incidence in patients with high-risk polyps, but it implies a major burden on colonoscopy units. Therefore, it should be targeted to individuals with a higher risk. Different societies have published guidelines on surveillance after resection of polyps, with notable discrepancies among them, and many recommendations come from low-quality evidence based on surrogate measures, such as risk of advanced adenoma, and not CRC risk. In this review, we aimed to summarize the evidence supporting post-polypectomy surveillance, compare the recently updated major guidelines, and discuss the existing discrepancies on this topic. Briefly, patients with adenomas ≥10 mm or high-grade dysplasia and patients with serrated polyps ≥10 mm or dysplasia are generally considered to have an increased risk of metachronous CRC and require surveillance, whereas the indication of surveillance is not clearly established in patients without these high-risk features.

View all citing articles on Scopus

: Conflicts of interest The authors disclose no conflicts.

: Funding This work was supported by grants as follows: Hawaii Colorectal Cancer Studies 2 and 3 are supported by National Institutes of Health (R01 CA60987). The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II cohort. Darmkrebs: Chancen der Verhütung durch Screening: German Research Council is supported by Deutsche Forschungsgemeinschaft (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). Diet, Activity and Lifestyle Study is supported by National Institutes of Health (R01 CA48998 to M. L. Slattery). Nurses’ Health Study and Health Professionals Follow-up Study: Health Professionals Follow-up Study is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), Nurses’ Health Study is supported by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003). Kentucky Case-Control Study was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8) and NCI R01CA136726. Melbourne Collaborative Cohort Study Axiom and OncoArray: Melbourne Collaborative Cohort Study cohort recruitment was funded by VicHealth and Cancer Council Victoria. The Melbourne Collaborative Cohort Study was further supported by Australian National Health and Medical Research Council grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Multi-Ethnic Cohort Study: National Institutes of Health (R37 CA54281, P01 CA033619, and R01 CA63464). Molecular Epidemiology of Colorectal Cancer: This work was supported by the National Institutes of Health, US Department of Health and Human Services (R01 CA81488 to SBG and GR). Newfoundland Case-Control Study: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, US Department of Health and Human Services (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the Newfoundland Case-Control Study samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics was supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility Prostate Cancer Genome-Wide Association Study (Yeager et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 2007;39:645–649), Cancer Genetic Markers of Susceptibility pancreatic cancer scan (PanScan) (Amundadottir et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet 2009;41:986–990, and Petersen et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet 2010;42:224–228), and the Lung Cancer and Smoking study (Landi et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am J Hum Genet 2009;85:679–691). The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health, Genes, Environment and Health Initiative Z01 CP 010200, National Institutes of Health U01 HG004446, and National Institutes of Health, Genes, Environment and Health Initiative U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. Vitamins and Lifestyle study was supported by National Institutes of Health (K05 CA154337). Women’s Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Genetics and Epidemiology of Colorectal Cancer Consortium: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930).

: Author names in bold designate shared co-first authorship.

View full text

Original ResearchFull Report: Basic and Translational—Alimentary TractDetermining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors

Background & Aims

Methods

Results

Conclusions

Graphical abstract

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

Gastroenterology

Gastroenterology

Gastroenterology

Genet Med

Gastroenterology

Am J Hum Genet

Colorectal Cancer Facts & Figures 2014-2016

Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement

JAMA

Screening for colorectal neoplasia

N Engl J Med

Electronic medical records for genetic research: results of the eMERGE consortium

Sci Transl Med

Genomic medicine, health information technology, and patient care

JAMA

Will knowledge of gene-based colorectal cancer disease risk influence quality of life and screening behavior? Findings from a population-based study

Public Health Genomics

The effect of referral for genetic counseling on genetic testing and surgical prevention in women at high risk for ovarian cancer: results from a randomized controlled trial

Cancer

Screening for colorectal cancer and evolving issues for physicians and patients: a review

JAMA

Risk prediction models for colorectal cancer: a review

Cancer Epidemiol Biomarkers Prev

Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals

Gut

Risk prediction models for colorectal cancer: a systematic review

Cancer Prev Res

Incremental benefits of screening colonoscopy over sigmoidoscopy in average-risk populations: a model-driven analysis

Cancer Causes Control

Estimation of benefits, burden, and harms of colorectal cancer screening strategies: modeling study for the US Preventive Services Task Force

JAMA

Risk model for colorectal cancer in Spanish population using environmental and genetic factors: results from the MCC-Spain study

Sci Rep

A new scoring system to predict the risk for high-risk adenoma and comparison of existing risk calculators

J Clin Gastroenterol

Assessing individual risk for high-risk colorectal adenoma at first-time screening colonoscopy

Int J Cancer

The Asia-Pacific Colorectal Screening score: a validated tool that stratifies risk for colorectal advanced neoplasia in asymptomatic Asian subjects

Gut

Original Research
Full Report: Basic and Translational—Alimentary Tract
Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors