Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals.
OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2013
|
| _version_ | 1797084313341132800 |
|---|---|
| author | Dunlop, MG Tenesa, A Farrington, S Ballereau, S Brewster, D Koessler, T Pharoah, P Schafmayer, C Hampe, J Völzke, H Chang-Claude, J Hoffmeister, M Brenner, H von Holst, S Picelli, S Lindblom, A Jenkins, M Hopper, J Casey, G Duggan, D Newcomb, P Abulí, A Bessa, X Ruiz-Ponte, C Castellví-Bel, S |
| author_facet | Dunlop, MG Tenesa, A Farrington, S Ballereau, S Brewster, D Koessler, T Pharoah, P Schafmayer, C Hampe, J Völzke, H Chang-Claude, J Hoffmeister, M Brenner, H von Holst, S Picelli, S Lindblom, A Jenkins, M Hopper, J Casey, G Duggan, D Newcomb, P Abulí, A Bessa, X Ruiz-Ponte, C Castellví-Bel, S |
| author_sort | Dunlop, MG |
| collection | OXFORD |
| description | OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance. |
| first_indexed | 2024-03-07T01:53:44Z |
| format | Journal article |
| id | oxford-uuid:9b04f7da-41ca-4dd4-96dd-648fe311e7e4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:53:44Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:9b04f7da-41ca-4dd4-96dd-648fe311e7e42022-03-27T00:25:43ZCumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9b04f7da-41ca-4dd4-96dd-648fe311e7e4EnglishSymplectic Elements at Oxford2013Dunlop, MGTenesa, AFarrington, SBallereau, SBrewster, DKoessler, TPharoah, PSchafmayer, CHampe, JVölzke, HChang-Claude, JHoffmeister, MBrenner, Hvon Holst, SPicelli, SLindblom, AJenkins, MHopper, JCasey, GDuggan, DNewcomb, PAbulí, ABessa, XRuiz-Ponte, CCastellví-Bel, SOBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance. |
| spellingShingle | Dunlop, MG Tenesa, A Farrington, S Ballereau, S Brewster, D Koessler, T Pharoah, P Schafmayer, C Hampe, J Völzke, H Chang-Claude, J Hoffmeister, M Brenner, H von Holst, S Picelli, S Lindblom, A Jenkins, M Hopper, J Casey, G Duggan, D Newcomb, P Abulí, A Bessa, X Ruiz-Ponte, C Castellví-Bel, S Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. |
| title | Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. |
| title_full | Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. |
| title_fullStr | Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. |
| title_full_unstemmed | Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. |
| title_short | Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals. |
| title_sort | cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals |
| work_keys_str_mv | AT dunlopmg cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT tenesaa cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT farringtons cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT ballereaus cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT brewsterd cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT koesslert cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT pharoahp cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT schafmayerc cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT hampej cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT volzkeh cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT changclaudej cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT hoffmeisterm cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT brennerh cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT vonholsts cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT picellis cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT lindbloma cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT jenkinsm cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT hopperj cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT caseyg cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT duggand cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT newcombp cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT abulia cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT bessax cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT ruizpontec cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals AT castellvibels cumulativeimpactofcommongeneticvariantsandotherriskfactorsoncolorectalcancerriskin42103individuals |