Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

Alan M. Pittman; Emily Webb; Luis Carvajal-Carmona; Kimberley Howarth; Maria Chiara Di Bernardo; Peter Broderick; Sarah Spain; Axel Walther; Amy Price; Kate Sullivan; Philip Twiss; Sarah Fielding; Andrew Rowan; Emma Jaeger; Jayaram Vijayakrishnan; Ian Chandler; Steven Penegar; Mobshra Qureshi; Steven Lubbe; Enric Domingo; Zoe Kemp; Ella Barclay; Wendy Wood; Lynn Martin; Maggie Gorman; Huw Thomas; Julian Peto; Timothy Bishop; Richard Gray; Eamonn R. Maher; Anneke Lucassen; David Kerr; Gareth R. Evans; Tom van Wezel; Hans Morreau; Juul T. Wijnen; John L. Hopper; Melissa C. Southey; Graham G. Giles; Gianluca Severi; Sergi Castellví-Bel; Clara Ruiz-Ponte; Angel Carracedo; Antoni Castells; Asta Försti; Kari Hemminki; Pavel Vodicka; Alessio Naccarati; Lara Lipton; Judy W C Ho; K. K. Cheng; Pak C. Sham; J. Luk; Jose A G Agúndez; Jose M. Ladero; Miguel de la Hoya; Trinidad Caldés; Iina Niittymäki; Sari Tuupanen; Auli Karhu; Lauri A. Aaltonen; Jean Baptiste Cazier; Ian P M Tomlinson; Richard S. Houlston

doi:10.1093/hmg/ddn267

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

Alan M. Pittman, Emily Webb, Luis Carvajal-Carmona, Kimberley Howarth, Maria Chiara Di Bernardo, Peter Broderick, Sarah Spain, Axel Walther, Amy Price, Kate Sullivan, Philip Twiss, Sarah Fielding, Andrew Rowan, Emma Jaeger, Jayaram Vijayakrishnan, Ian Chandler, Steven Penegar, Mobshra Qureshi, Steven Lubbe, Enric DomingoZoe Kemp, Ella Barclay, Wendy Wood, Lynn Martin, Maggie Gorman, Huw Thomas, Julian Peto, Timothy Bishop, Richard Gray, Eamonn R. Maher, Anneke Lucassen, David Kerr, Gareth R. Evans, Tom van Wezel, Hans Morreau, Juul T. Wijnen, John L. Hopper, Melissa C. Southey, Graham G. Giles, Gianluca Severi, Sergi Castellví-Bel, Clara Ruiz-Ponte, Angel Carracedo, Antoni Castells, Asta Försti, Kari Hemminki, Pavel Vodicka, Alessio Naccarati, Lara Lipton, Judy W C Ho, K. K. Cheng, Pak C. Sham, J. Luk, Jose A G Agúndez, Jose M. Ladero, Miguel de la Hoya, Trinidad Caldés, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri A. Aaltonen, Jean Baptiste Cazier, Ian P M Tomlinson, Richard S. Houlston^*

^*Corresponding author for this work

Neurology

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

63 Scopus citations

Abstract

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 × 10^-12) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR_{per allele} = 1.19; 95% CI: 1.15-1.23; P_trend = 7.4 × 10^-24). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

Original language	English (US)
Pages (from-to)	3720-3727
Number of pages	8
Journal	Human molecular genetics
Volume	17
Issue number	23
DOIs	https://doi.org/10.1093/hmg/ddn267
State	Published - 2008

Funding

Cancer Research UK provided principal funding for this study. Institute of Cancer Research: Additional funding was provided by the European Union (CPRB LSHC-CT-2004-503465), the Bobby Moore Fund, CORE and the Thomas Falknor Fund. I.C. was in receipt of a clinical training fellowship from St. George’s Hospital Medical School. London Institute: Additional funding was provided by CORE and the Bobby Moore Fund. Barcelona: We are sincerely grateful to all patients participating in this study that were recruited in 25 Spanish hospitals as part of the EPI-COLON project. This work was supported by grants from the Fondo de Investigación Sanitaria (03/0070, 05/0071 and 05/ 2031), from the Ministerio de Educación y Ciencia (SAF 04-07190 and 07-64873), the Asociación Española contra el Cáncer, from Merck, Co, from the Xunta de Galicia (PGI-DIT07PXIB9101209PR), from Fundacion Olga Torres (S.C.-B.), and from Fundación de Investigación Médica Mútua Madrileña (C.R.-P.). CIBEREHD and CIBERER are funded by the Instituto de Salud Carlos III. S.C.-B. is supported by a contract from the Fondo de Investigación Sanitaria (CP 03-0070, Ministerio de Sanidad). Extremadura: Work was supported by grants FIS 051056 and RD07/0064/ 0016 from Instituto de Salud Carlos III, Madrid, Spain. Finland: This work was supported by grants from Academy of Finland (Finnish Centre of Excellence Program 2006–2011), the Finnish Cancer Society, the Sigrid Juselius Foundation and the European Commission 9LSHG-CT-2004-512142). Heidelberg: Supported by Deutsche Krebshilfe and the Swedish Cancer Society. Kiel: This study was supported by the German Ministry of Education and Research through the National Genome Research Network through the POPGEN biobank project (01GS0426, 01GR0468) and the Medical Faculty, Kiel. The SHIP recuit-ment project is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Leiden: DFCCS was supported by Dutch Cancer Society grant UL2005-3247 and approved by the local Medical Ethical Committee (protocol P01.019); samples were handled according to Code Proper Secondary Use of Human Tissue by the Dutch Federation of Medical Sciences (www.federa.org). Madrid: Work was supported by the Fondo Investigacion Sanitaria (PI070316 and RD06/0020/0021). Melbourne: The Melbourne Collaborative Cohort Study is supported by National Health and Medical Research Council (NHMRC) grants 209057, 251533 and 396414 and receives core funding and infrastructure support from the The Cancer Council Victoria. J.L.H. is a NHMRC Australia Fellow and M.C.S. is a NHMRC Senior Research Fellow. We would like to acknowledge Mr Fabrice Odefrey for performing the genotyping. Prague: Supported by the grant GACR 310/07/1430.

ASJC Scopus subject areas

Genetics(clinical)
Genetics
Molecular Biology

UN SDGs

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

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10.1093/hmg/ddn267

Cite this

Pittman, A. M., Webb, E., Carvajal-Carmona, L., Howarth, K., Di Bernardo, M. C., Broderick, P., Spain, S., Walther, A., Price, A., Sullivan, K., Twiss, P., Fielding, S., Rowan, A., Jaeger, E., Vijayakrishnan, J., Chandler, I., Penegar, S., Qureshi, M., Lubbe, S., ... Houlston, R. S. (2008). Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer. Human molecular genetics, 17(23), 3720-3727. https://doi.org/10.1093/hmg/ddn267

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title = "Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer",

abstract = "The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 × 10-12) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15-1.23; Ptrend = 7.4 × 10-24). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.",

author = "Pittman, {Alan M.} and Emily Webb and Luis Carvajal-Carmona and Kimberley Howarth and {Di Bernardo}, {Maria Chiara} and Peter Broderick and Sarah Spain and Axel Walther and Amy Price and Kate Sullivan and Philip Twiss and Sarah Fielding and Andrew Rowan and Emma Jaeger and Jayaram Vijayakrishnan and Ian Chandler and Steven Penegar and Mobshra Qureshi and Steven Lubbe and Enric Domingo and Zoe Kemp and Ella Barclay and Wendy Wood and Lynn Martin and Maggie Gorman and Huw Thomas and Julian Peto and Timothy Bishop and Richard Gray and Maher, {Eamonn R.} and Anneke Lucassen and David Kerr and Evans, {Gareth R.} and {van Wezel}, Tom and Hans Morreau and Wijnen, {Juul T.} and Hopper, {John L.} and Southey, {Melissa C.} and Giles, {Graham G.} and Gianluca Severi and Sergi Castellv{\'i}-Bel and Clara Ruiz-Ponte and Angel Carracedo and Antoni Castells and Asta F{\"o}rsti and Kari Hemminki and Pavel Vodicka and Alessio Naccarati and Lara Lipton and Ho, {Judy W C} and Cheng, {K. K.} and Sham, {Pak C.} and J. Luk and Ag{\'u}ndez, {Jose A G} and Ladero, {Jose M.} and {de la Hoya}, Miguel and Trinidad Cald{\'e}s and Iina Niittym{\"a}ki and Sari Tuupanen and Auli Karhu and Aaltonen, {Lauri A.} and Cazier, {Jean Baptiste} and Tomlinson, {Ian P M} and Houlston, {Richard S.}",

note = "Funding Information: Cancer Research UK provided principal funding for this study. Institute of Cancer Research: Additional funding was provided by the European Union (CPRB LSHC-CT-2004-503465), the Bobby Moore Fund, CORE and the Thomas Falknor Fund. I.C. was in receipt of a clinical training fellowship from St. George{\textquoteright}s Hospital Medical School. London Institute: Additional funding was provided by CORE and the Bobby Moore Fund. Barcelona: We are sincerely grateful to all patients participating in this study that were recruited in 25 Spanish hospitals as part of the EPI-COLON project. This work was supported by grants from the Fondo de Investigaci{\'o}n Sanitaria (03/0070, 05/0071 and 05/ 2031), from the Ministerio de Educaci{\'o}n y Ciencia (SAF 04-07190 and 07-64873), the Asociaci{\'o}n Espa{\~n}ola contra el C{\'a}ncer, from Merck, Co, from the Xunta de Galicia (PGI-DIT07PXIB9101209PR), from Fundacion Olga Torres (S.C.-B.), and from Fundaci{\'o}n de Investigaci{\'o}n M{\'e}dica M{\'u}tua Madrile{\~n}a (C.R.-P.). CIBEREHD and CIBERER are funded by the Instituto de Salud Carlos III. S.C.-B. is supported by a contract from the Fondo de Investigaci{\'o}n Sanitaria (CP 03-0070, Ministerio de Sanidad). Extremadura: Work was supported by grants FIS 051056 and RD07/0064/ 0016 from Instituto de Salud Carlos III, Madrid, Spain. Finland: This work was supported by grants from Academy of Finland (Finnish Centre of Excellence Program 2006–2011), the Finnish Cancer Society, the Sigrid Juselius Foundation and the European Commission 9LSHG-CT-2004-512142). Heidelberg: Supported by Deutsche Krebshilfe and the Swedish Cancer Society. Kiel: This study was supported by the German Ministry of Education and Research through the National Genome Research Network through the POPGEN biobank project (01GS0426, 01GR0468) and the Medical Faculty, Kiel. The SHIP recuit-ment project is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Leiden: DFCCS was supported by Dutch Cancer Society grant UL2005-3247 and approved by the local Medical Ethical Committee (protocol P01.019); samples were handled according to Code Proper Secondary Use of Human Tissue by the Dutch Federation of Medical Sciences (www.federa.org). Madrid: Work was supported by the Fondo Investigacion Sanitaria (PI070316 and RD06/0020/0021). Melbourne: The Melbourne Collaborative Cohort Study is supported by National Health and Medical Research Council (NHMRC) grants 209057, 251533 and 396414 and receives core funding and infrastructure support from the The Cancer Council Victoria. J.L.H. is a NHMRC Australia Fellow and M.C.S. is a NHMRC Senior Research Fellow. We would like to acknowledge Mr Fabrice Odefrey for performing the genotyping. Prague: Supported by the grant GACR 310/07/1430.",

year = "2008",

doi = "10.1093/hmg/ddn267",

language = "English (US)",

volume = "17",

pages = "3720--3727",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "23",

}

Pittman, AM, Webb, E, Carvajal-Carmona, L, Howarth, K, Di Bernardo, MC, Broderick, P, Spain, S, Walther, A, Price, A, Sullivan, K, Twiss, P, Fielding, S, Rowan, A, Jaeger, E, Vijayakrishnan, J, Chandler, I, Penegar, S, Qureshi, M, Lubbe, S, Domingo, E, Kemp, Z, Barclay, E, Wood, W, Martin, L, Gorman, M, Thomas, H, Peto, J, Bishop, T, Gray, R, Maher, ER, Lucassen, A, Kerr, D, Evans, GR, van Wezel, T, Morreau, H, Wijnen, JT, Hopper, JL, Southey, MC, Giles, GG, Severi, G, Castellví-Bel, S, Ruiz-Ponte, C, Carracedo, A, Castells, A, Försti, A, Hemminki, K, Vodicka, P, Naccarati, A, Lipton, L, Ho, JWC, Cheng, KK, Sham, PC, Luk, J, Agúndez, JAG, Ladero, JM, de la Hoya, M, Caldés, T, Niittymäki, I, Tuupanen, S, Karhu, A, Aaltonen, LA, Cazier, JB, Tomlinson, IPM & Houlston, RS 2008, 'Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer', Human molecular genetics, vol. 17, no. 23, pp. 3720-3727. https://doi.org/10.1093/hmg/ddn267

TY - JOUR

T1 - Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

AU - Pittman, Alan M.

AU - Webb, Emily

AU - Carvajal-Carmona, Luis

AU - Howarth, Kimberley

AU - Di Bernardo, Maria Chiara

AU - Broderick, Peter

AU - Spain, Sarah

AU - Walther, Axel

AU - Price, Amy

AU - Sullivan, Kate

AU - Twiss, Philip

AU - Fielding, Sarah

AU - Rowan, Andrew

AU - Jaeger, Emma

AU - Vijayakrishnan, Jayaram

AU - Chandler, Ian

AU - Penegar, Steven

AU - Qureshi, Mobshra

AU - Lubbe, Steven

AU - Domingo, Enric

AU - Kemp, Zoe

AU - Barclay, Ella

AU - Wood, Wendy

AU - Martin, Lynn

AU - Gorman, Maggie

AU - Thomas, Huw

AU - Peto, Julian

AU - Bishop, Timothy

AU - Gray, Richard

AU - Maher, Eamonn R.

AU - Lucassen, Anneke

AU - Kerr, David

AU - Evans, Gareth R.

AU - van Wezel, Tom

AU - Morreau, Hans

AU - Wijnen, Juul T.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Giles, Graham G.

AU - Severi, Gianluca

AU - Castellví-Bel, Sergi

AU - Ruiz-Ponte, Clara

AU - Carracedo, Angel

AU - Castells, Antoni

AU - Försti, Asta

AU - Hemminki, Kari

AU - Vodicka, Pavel

AU - Naccarati, Alessio

AU - Lipton, Lara

AU - Ho, Judy W C

AU - Cheng, K. K.

AU - Sham, Pak C.

AU - Luk, J.

AU - Agúndez, Jose A G

AU - Ladero, Jose M.

AU - de la Hoya, Miguel

AU - Caldés, Trinidad

AU - Niittymäki, Iina

AU - Tuupanen, Sari

AU - Karhu, Auli

AU - Aaltonen, Lauri A.

AU - Cazier, Jean Baptiste

AU - Tomlinson, Ian P M

AU - Houlston, Richard S.

N1 - Funding Information: Cancer Research UK provided principal funding for this study. Institute of Cancer Research: Additional funding was provided by the European Union (CPRB LSHC-CT-2004-503465), the Bobby Moore Fund, CORE and the Thomas Falknor Fund. I.C. was in receipt of a clinical training fellowship from St. George’s Hospital Medical School. London Institute: Additional funding was provided by CORE and the Bobby Moore Fund. Barcelona: We are sincerely grateful to all patients participating in this study that were recruited in 25 Spanish hospitals as part of the EPI-COLON project. This work was supported by grants from the Fondo de Investigación Sanitaria (03/0070, 05/0071 and 05/ 2031), from the Ministerio de Educación y Ciencia (SAF 04-07190 and 07-64873), the Asociación Española contra el Cáncer, from Merck, Co, from the Xunta de Galicia (PGI-DIT07PXIB9101209PR), from Fundacion Olga Torres (S.C.-B.), and from Fundación de Investigación Médica Mútua Madrileña (C.R.-P.). CIBEREHD and CIBERER are funded by the Instituto de Salud Carlos III. S.C.-B. is supported by a contract from the Fondo de Investigación Sanitaria (CP 03-0070, Ministerio de Sanidad). Extremadura: Work was supported by grants FIS 051056 and RD07/0064/ 0016 from Instituto de Salud Carlos III, Madrid, Spain. Finland: This work was supported by grants from Academy of Finland (Finnish Centre of Excellence Program 2006–2011), the Finnish Cancer Society, the Sigrid Juselius Foundation and the European Commission 9LSHG-CT-2004-512142). Heidelberg: Supported by Deutsche Krebshilfe and the Swedish Cancer Society. Kiel: This study was supported by the German Ministry of Education and Research through the National Genome Research Network through the POPGEN biobank project (01GS0426, 01GR0468) and the Medical Faculty, Kiel. The SHIP recuit-ment project is funded by the Federal Ministry of Education and Research (ZZ9603), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Leiden: DFCCS was supported by Dutch Cancer Society grant UL2005-3247 and approved by the local Medical Ethical Committee (protocol P01.019); samples were handled according to Code Proper Secondary Use of Human Tissue by the Dutch Federation of Medical Sciences (www.federa.org). Madrid: Work was supported by the Fondo Investigacion Sanitaria (PI070316 and RD06/0020/0021). Melbourne: The Melbourne Collaborative Cohort Study is supported by National Health and Medical Research Council (NHMRC) grants 209057, 251533 and 396414 and receives core funding and infrastructure support from the The Cancer Council Victoria. J.L.H. is a NHMRC Australia Fellow and M.C.S. is a NHMRC Senior Research Fellow. We would like to acknowledge Mr Fabrice Odefrey for performing the genotyping. Prague: Supported by the grant GACR 310/07/1430.

PY - 2008

Y1 - 2008

N2 - The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 × 10-12) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15-1.23; Ptrend = 7.4 × 10-24). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

AB - The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 × 10-12) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (ORper allele = 1.19; 95% CI: 1.15-1.23; Ptrend = 7.4 × 10-24). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

UR - http://www.scopus.com/inward/record.url?scp=56049119387&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=56049119387&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddn267

DO - 10.1093/hmg/ddn267

M3 - Article

C2 - 18753146

AN - SCOPUS:56049119387

SN - 0964-6906

VL - 17

SP - 3720

EP - 3727

JO - Human molecular genetics

JF - Human molecular genetics

IS - 23

ER -

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

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