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

Malcolm G. Dunlop; Albert Tenesa; Susan M. Farrington; Stephane Ballereau; David H. Brewster; Thibaud Koessler; Paul Pharoah; Clemens Schafmayer; Jochen Hampe; Henry Völzke; Jenny Chang-Claude; Michael Hoffmeister; Hermann Brenner; Susanna Von Holst; Simone Picelli; Annika Lindblom; Mark A. Jenkins; John L. Hopper; Graham Casey; David Duggan; Polly A. Newcomb; Anna Abulí; Xavier Bessa; Clara Ruiz-Ponte; Sergi Castellví-Bel; Iina Niittymäki; Sari Tuupanen; Auli Karhu; Lauri Aaltonen; Brent Zanke; Tom Hudson; Steven Gallinger; Ella Barclay; Lynn Martin; Maggie Gorman; Luis Carvajal-Carmona; Axel Walther; David Kerr; Steven Lubbe; Peter Broderick; Ian Chandler; Alan Pittman; Steven Penegar; Harry Campbell; Ian Tomlinson; Richard S. Houlston

doi:10.1136/gutjnl-2011-300537

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

Malcolm G. Dunlop^*, Albert Tenesa, Susan M. Farrington, Stephane Ballereau, David H. Brewster, Thibaud Koessler, Paul Pharoah, Clemens Schafmayer, Jochen Hampe, Henry Völzke, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Susanna Von Holst, Simone Picelli, Annika Lindblom, Mark A. Jenkins, John L. Hopper, Graham Casey, David DugganPolly A. Newcomb, Anna Abulí, Xavier Bessa, Clara Ruiz-Ponte, Sergi Castellví-Bel, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri Aaltonen, Brent Zanke, Tom Hudson, Steven Gallinger, Ella Barclay, Lynn Martin, Maggie Gorman, Luis Carvajal-Carmona, Axel Walther, David Kerr, Steven Lubbe, Peter Broderick, Ian Chandler, Alan Pittman, Steven Penegar, Harry Campbell, Ian Tomlinson, Richard S. Houlston

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

101 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	871-881
Number of pages	11
Journal	Gut
Volume	62
Issue number	6
DOIs	https://doi.org/10.1136/gutjnl-2011-300537
State	Published - Jun 2013

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Gastroenterology

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/gutjnl-2011-300537

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Dunlop, M. G., Tenesa, A., Farrington, S. M., Ballereau, S., Brewster, D. H., 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. A., Hopper, J. L., Casey, G., ... Houlston, R. S. (2013). Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals. Gut, 62(6), 871-881. https://doi.org/10.1136/gutjnl-2011-300537

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

abstract = "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.",

author = "Dunlop, {Malcolm G.} and Albert Tenesa and Farrington, {Susan M.} and Stephane Ballereau and Brewster, {David H.} and Thibaud Koessler and Paul Pharoah and Clemens Schafmayer and Jochen Hampe and Henry V{\"o}lzke and Jenny Chang-Claude and Michael Hoffmeister and Hermann Brenner and {Von Holst}, Susanna and Simone Picelli and Annika Lindblom and Jenkins, {Mark A.} and Hopper, {John L.} and Graham Casey and David Duggan and Newcomb, {Polly A.} and Anna Abul{\'i} and Xavier Bessa and Clara Ruiz-Ponte and Sergi Castellv{\'i}-Bel and Iina Niittym{\"a}ki and Sari Tuupanen and Auli Karhu and Lauri Aaltonen and Brent Zanke and Tom Hudson and Steven Gallinger and Ella Barclay and Lynn Martin and Maggie Gorman and Luis Carvajal-Carmona and Axel Walther and David Kerr and Steven Lubbe and Peter Broderick and Ian Chandler and Alan Pittman and Steven Penegar and Harry Campbell and Ian Tomlinson and Houlston, {Richard S.}",

year = "2013",

month = jun,

doi = "10.1136/gutjnl-2011-300537",

language = "English (US)",

volume = "62",

pages = "871--881",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "6",

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Dunlop, MG, Tenesa, A, Farrington, SM, Ballereau, S, Brewster, DH, 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, MA, Hopper, JL, Casey, G, Duggan, D, Newcomb, PA, Abulí, A, Bessa, X, Ruiz-Ponte, C, Castellví-Bel, S, Niittymäki, I, Tuupanen, S, Karhu, A, Aaltonen, L, Zanke, B, Hudson, T, Gallinger, S, Barclay, E, Martin, L, Gorman, M, Carvajal-Carmona, L, Walther, A, Kerr, D, Lubbe, S, Broderick, P, Chandler, I, Pittman, A, Penegar, S, Campbell, H, Tomlinson, I & Houlston, RS 2013, 'Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals', Gut, vol. 62, no. 6, pp. 871-881. https://doi.org/10.1136/gutjnl-2011-300537

TY - JOUR

T1 - Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42 103 individuals

AU - Dunlop, Malcolm G.

AU - Tenesa, Albert

AU - Farrington, Susan M.

AU - Ballereau, Stephane

AU - Brewster, David H.

AU - Koessler, Thibaud

AU - Pharoah, Paul

AU - Schafmayer, Clemens

AU - Hampe, Jochen

AU - Völzke, Henry

AU - Chang-Claude, Jenny

AU - Hoffmeister, Michael

AU - Brenner, Hermann

AU - Von Holst, Susanna

AU - Picelli, Simone

AU - Lindblom, Annika

AU - Jenkins, Mark A.

AU - Hopper, John L.

AU - Casey, Graham

AU - Duggan, David

AU - Newcomb, Polly A.

AU - Abulí, Anna

AU - Bessa, Xavier

AU - Ruiz-Ponte, Clara

AU - Castellví-Bel, Sergi

AU - Niittymäki, Iina

AU - Tuupanen, Sari

AU - Karhu, Auli

AU - Aaltonen, Lauri

AU - Zanke, Brent

AU - Hudson, Tom

AU - Gallinger, Steven

AU - Barclay, Ella

AU - Martin, Lynn

AU - Gorman, Maggie

AU - Carvajal-Carmona, Luis

AU - Walther, Axel

AU - Kerr, David

AU - Lubbe, Steven

AU - Broderick, Peter

AU - Chandler, Ian

AU - Pittman, Alan

AU - Penegar, Steven

AU - Campbell, Harry

AU - Tomlinson, Ian

AU - Houlston, Richard S.

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

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

Abstract

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