Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

Timothy H.T. Cheng; Maggie Gorman; Lynn Martin; Ella Barclay; Graham Casey; Polly A. Newcomb; David V. Conti; Fredrick R. Schumacher; Steve Gallinger; Noralane M. Lindor; John Hopper; Mark Jenkins; David J. Hunter; Peter Kraft; Kevin B. Jacobs; David G. Cox; Meredith Yeager; Susan E. Hankinson; Sholom Wacholder; Zhaoming Wang; Robert Welch; Amy Hutchinson; Junwen Wang; Kai Yu; Nilanjan Chatterjee; Nick Orr; Walter C. Willett; Graham A. Colditz; Regina G. Ziegler; Christine D. Berg; Saundra S. Buys; Catherine A. McCarty; Heather Spencer Feigelson; Eugenia E. Calle; Michael J. Thun; Richard B. Hayes; Margaret Tucker; Daniela S. Gerhard; Joseph F. Fraumeni; Robert N. Hoover; Gilles Thomas; Stephen J. Chanock; Julia Ciampa; Jesus Gonzalez-Bosquet; Sonja Berndt; Laufey Amundadottir; W. Ryan Diver; Demetrius Albanes; Jarmo Virtamo; Stephanie J. Weinstein; Geraldine Cancel-Tassin; Olivier Cussenot; Antoine Valeri; Gerald L. Andriole; E. David Crawford; Christopher A. Haiman; Brian Henderson; Laurence Kolonel; Loic Le Marchand; Afshan Siddiq; Elio Riboli; Timothy J. Key; Rudolf Kaaks; William Isaacs; Sarah Isaacs; Kathleen E. Wiley; Henrik Gronberg; Fredrik Wiklund; Pär Stattin; Jianfeng Xu; S. Lilly Zheng; Jielin Sun; Lars J. Vatten; Kristian Hveem; Merethe Kumle; Mark P. Purdue; Mattias Johansson; Diana Zelenika; Jorge R. Toro; Ghislaine Scelo; Lee E. Moore; Egor Prokhortchouk; Xifeng Wu; Lambertus A. Kiemeney; Valerie Gaborieau; Wong Ho Chow; David Zaridze; Vsevolod Matveev; Jan Lubinski; Joanna Trubicka; Neonila Szeszenia-Dabrowska; Jolanta Lissowska; Péter Rudnai; Eleonora Fabianova; Alexandru Bucur; Vladimir Bencko; Lenka Foretova; Vladimir Janout; Paolo Boffetta; Joanne S. Colt; Faith G. Davis; Kendra L. Schwartz; Rosamonde E. Banks; Peter J. Selby; Patricia Harnden; Ann W. Hsing; Robert L. Grubb; Heiner Boeing; Paolo Vineis; Franҫoise Clavel-Chapelon; Domenico Palli; Rosario Tumino; Vittorio Krogh; Salvatore Panico; Eric J. Duell; José Ramón Quirós; Maria José Sanchez; Carmen Navarro; Eva Ardanaz; Miren Dorronsoro; Kay Tee Khaw; Naomi E. Allen; H. Bas Bueno-de-Mesquita; Petra H.M. Peeters; Dimitrios Trichopoulos; Jakob Linseisen; Börje Ljungberg; Kim Overvad; Anne Tjønneland; Isabelle Romieu; Anush Mukeria; Oxana Shangina; Victoria L. Stevens; Susan M. Gapstur; Paul D. Pharoah; Douglas F. Easton; Inger Njølstad; Grethe S. Tell; Camilla Stoltenberg; Rajiv Kumar; Kvetoslava Koppova; Simone Benhamou; Egbert Oosterwijk; Sita H. Vermeulen; Katja K.H. Aben; Saskia L. Van Der Marel; Yuanqing Ye; Christopher G. Wood; Xia Pu; Alexander M. Mazur; Eugenia S. Boulygina; Nikolai N. Chekanov; Mario Foglio; Doris Lechner; Ivo Gut; Simon Heath; Hélène Blanche; Konstantin G. Skryabin; James D. McKay; Nathaniel Rothman; Mark Lathrop; Paul Brennan; Brian Saunders; Huw Thomas; Sue Clark; Ian Tomlinson

doi:10.1038/ejhg.2014.74

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

Timothy H.T. Cheng, Maggie Gorman, Lynn Martin, Ella Barclay, Graham Casey, Polly A. Newcomb, David V. Conti, Fredrick R. Schumacher, Steve Gallinger, Noralane M. Lindor, John Hopper, Mark Jenkins, David J. Hunter, Peter Kraft, Kevin B. Jacobs, David G. Cox, Meredith Yeager, Susan E. Hankinson, Sholom Wacholder, Zhaoming WangRobert Welch, Amy Hutchinson, Junwen Wang, Kai Yu, Nilanjan Chatterjee, Nick Orr, Walter C. Willett, Graham A. Colditz, Regina G. Ziegler, Christine D. Berg, Saundra S. Buys, Catherine A. McCarty, Heather Spencer Feigelson, Eugenia E. Calle, Michael J. Thun, Richard B. Hayes, Margaret Tucker, Daniela S. Gerhard, Joseph F. Fraumeni, Robert N. Hoover, Gilles Thomas, Stephen J. Chanock, Julia Ciampa, Jesus Gonzalez-Bosquet, Sonja Berndt, Laufey Amundadottir, W. Ryan Diver, Demetrius Albanes, Jarmo Virtamo, Stephanie J. Weinstein, Geraldine Cancel-Tassin, Olivier Cussenot, Antoine Valeri, Gerald L. Andriole, E. David Crawford, Christopher A. Haiman, Brian Henderson, Laurence Kolonel, Loic Le Marchand, Afshan Siddiq, Elio Riboli, Timothy J. Key, Rudolf Kaaks, William Isaacs, Sarah Isaacs, Kathleen E. Wiley, Henrik Gronberg, Fredrik Wiklund, Pär Stattin, Jianfeng Xu, S. Lilly Zheng, Jielin Sun, Lars J. Vatten, Kristian Hveem, Merethe Kumle, Mark P. Purdue, Mattias Johansson, Diana Zelenika, Jorge R. Toro, Ghislaine Scelo, Lee E. Moore, Egor Prokhortchouk, Xifeng Wu, Lambertus A. Kiemeney, Valerie Gaborieau, Wong Ho Chow, David Zaridze, Vsevolod Matveev, Jan Lubinski, Joanna Trubicka, Neonila Szeszenia-Dabrowska, Jolanta Lissowska, Péter Rudnai, Eleonora Fabianova, Alexandru Bucur, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Paolo Boffetta, Joanne S. Colt, Faith G. Davis, Kendra L. Schwartz, Rosamonde E. Banks, Peter J. Selby, Patricia Harnden, Ann W. Hsing, Robert L. Grubb, Heiner Boeing, Paolo Vineis, Franҫoise Clavel-Chapelon, Domenico Palli, Rosario Tumino, Vittorio Krogh, Salvatore Panico, Eric J. Duell, José Ramón Quirós, Maria José Sanchez, Carmen Navarro, Eva Ardanaz, Miren Dorronsoro, Kay Tee Khaw, Naomi E. Allen, H. Bas Bueno-de-Mesquita, Petra H.M. Peeters, Dimitrios Trichopoulos, Jakob Linseisen, Börje Ljungberg, Kim Overvad, Anne Tjønneland, Isabelle Romieu, Anush Mukeria, Oxana Shangina, Victoria L. Stevens, Susan M. Gapstur, Paul D. Pharoah, Douglas F. Easton, Inger Njølstad, Grethe S. Tell, Camilla Stoltenberg, Rajiv Kumar, Kvetoslava Koppova, Simone Benhamou, Egbert Oosterwijk, Sita H. Vermeulen, Katja K.H. Aben, Saskia L. Van Der Marel, Yuanqing Ye, Christopher G. Wood, Xia Pu, Alexander M. Mazur, Eugenia S. Boulygina, Nikolai N. Chekanov, Mario Foglio, Doris Lechner, Ivo Gut, Simon Heath, Hélène Blanche, Konstantin G. Skryabin, James D. McKay, Nathaniel Rothman, Mark Lathrop, Paul Brennan, Brian Saunders, Huw Thomas, Sue Clark, Ian Tomlinson

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

12 Scopus citations

Abstract

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10 ^-7 ). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

Original language	English (US)
Pages (from-to)	260-263
Number of pages	4
Journal	European Journal of Human Genetics
Volume	23
Issue number	2
DOIs	https://doi.org/10.1038/ejhg.2014.74
State	Published - Feb 20 2015

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1038/ejhg.2014.74

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Cheng, T. H. T., Gorman, M., Martin, L., Barclay, E., Casey, G., Newcomb, P. A., Conti, D. V., Schumacher, F. R., Gallinger, S., Lindor, N. M., Hopper, J., Jenkins, M., Hunter, D. J., Kraft, P., Jacobs, K. B., Cox, D. G., Yeager, M., Hankinson, S. E., Wacholder, S., ... Tomlinson, I. (2015). Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP. European Journal of Human Genetics, 23(2), 260-263. https://doi.org/10.1038/ejhg.2014.74

Cheng, THT, Gorman, M, Martin, L, Barclay, E, Casey, G, Newcomb, PA, Conti, DV, Schumacher, FR, Gallinger, S, Lindor, NM, Hopper, J, Jenkins, M, Hunter, DJ, Kraft, P, Jacobs, KB, Cox, DG, Yeager, M, Hankinson, SE, Wacholder, S, Wang, Z, Welch, R, Hutchinson, A, Wang, J, Yu, K, Chatterjee, N, Orr, N, Willett, WC, Colditz, GA, Ziegler, RG, Berg, CD, Buys, SS, McCarty, CA, Feigelson, HS, Calle, EE, Thun, MJ, Hayes, RB, Tucker, M, Gerhard, DS, Fraumeni, JF, Hoover, RN, Thomas, G, Chanock, SJ, Ciampa, J, Gonzalez-Bosquet, J, Berndt, S, Amundadottir, L, Diver, WR, Albanes, D, Virtamo, J, Weinstein, SJ, Cancel-Tassin, G, Cussenot, O, Valeri, A, Andriole, GL, Crawford, ED, Haiman, CA, Henderson, B, Kolonel, L, Marchand, LL, Siddiq, A, Riboli, E, Key, TJ, Kaaks, R, Isaacs, W, Isaacs, S, Wiley, KE, Gronberg, H, Wiklund, F, Stattin, P, Xu, J, Zheng, SL, Sun, J, Vatten, LJ, Hveem, K, Kumle, M, Purdue, MP, Johansson, M, Zelenika, D, Toro, JR, Scelo, G, Moore, LE, Prokhortchouk, E, Wu, X, Kiemeney, LA, Gaborieau, V, Chow, WH, Zaridze, D, Matveev, V, Lubinski, J, Trubicka, J, Szeszenia-Dabrowska, N, Lissowska, J, Rudnai, P, Fabianova, E, Bucur, A, Bencko, V, Foretova, L, Janout, V, Boffetta, P, Colt, JS, Davis, FG, Schwartz, KL, Banks, RE, Selby, PJ, Harnden, P, Hsing, AW, Grubb, RL, Boeing, H, Vineis, P, Clavel-Chapelon, F, Palli, D, Tumino, R, Krogh, V, Panico, S, Duell, EJ, Quirós, JR, Sanchez, MJ, Navarro, C, Ardanaz, E, Dorronsoro, M, Khaw, KT, Allen, NE, Bueno-de-Mesquita, HB, Peeters, PHM, Trichopoulos, D, Linseisen, J, Ljungberg, B, Overvad, K, Tjønneland, A, Romieu, I, Mukeria, A, Shangina, O, Stevens, VL, Gapstur, SM, Pharoah, PD, Easton, DF, Njølstad, I, Tell, GS, Stoltenberg, C, Kumar, R, Koppova, K, Benhamou, S, Oosterwijk, E, Vermeulen, SH, Aben, KKH, Van Der Marel, SL, Ye, Y, Wood, CG, Pu, X, Mazur, AM, Boulygina, ES, Chekanov, NN, Foglio, M, Lechner, D, Gut, I, Heath, S, Blanche, H, Skryabin, KG, McKay, JD, Rothman, N, Lathrop, M, Brennan, P, Saunders, B, Thomas, H, Clark, S & Tomlinson, I 2015, 'Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP', European Journal of Human Genetics, vol. 23, no. 2, pp. 260-263. https://doi.org/10.1038/ejhg.2014.74

@article{208477f5cf714f8795eb3c35268e8522,

title = "Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP",

abstract = " The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10 -7 ). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.",

author = "Cheng, {Timothy H.T.} and Maggie Gorman and Lynn Martin and Ella Barclay and Graham Casey and Newcomb, {Polly A.} and Conti, {David V.} and Schumacher, {Fredrick R.} and Steve Gallinger and Lindor, {Noralane M.} and John Hopper and Mark Jenkins and Hunter, {David J.} and Peter Kraft and Jacobs, {Kevin B.} and Cox, {David G.} and Meredith Yeager and Hankinson, {Susan E.} and Sholom Wacholder and Zhaoming Wang and Robert Welch and Amy Hutchinson and Junwen Wang and Kai Yu and Nilanjan Chatterjee and Nick Orr and Willett, {Walter C.} and Colditz, {Graham A.} and Ziegler, {Regina G.} and Berg, {Christine D.} and Buys, {Saundra S.} and McCarty, {Catherine A.} and Feigelson, {Heather Spencer} and Calle, {Eugenia E.} and Thun, {Michael J.} and Hayes, {Richard B.} and Margaret Tucker and Gerhard, {Daniela S.} and Fraumeni, {Joseph F.} and Hoover, {Robert N.} and Gilles Thomas and Chanock, {Stephen J.} and Julia Ciampa and Jesus Gonzalez-Bosquet and Sonja Berndt and Laufey Amundadottir and Diver, {W. Ryan} and Demetrius Albanes and Jarmo Virtamo and Weinstein, {Stephanie J.} and Geraldine Cancel-Tassin and Olivier Cussenot and Antoine Valeri and Andriole, {Gerald L.} and Crawford, {E. David} and Haiman, {Christopher A.} and Brian Henderson and Laurence Kolonel and Marchand, {Loic Le} and Afshan Siddiq and Elio Riboli and Key, {Timothy J.} and Rudolf Kaaks and William Isaacs and Sarah Isaacs and Wiley, {Kathleen E.} and Henrik Gronberg and Fredrik Wiklund and P{\"a}r Stattin and Jianfeng Xu and Zheng, {S. Lilly} and Jielin Sun and Vatten, {Lars J.} and Kristian Hveem and Merethe Kumle and Purdue, {Mark P.} and Mattias Johansson and Diana Zelenika and Toro, {Jorge R.} and Ghislaine Scelo and Moore, {Lee E.} and Egor Prokhortchouk and Xifeng Wu and Kiemeney, {Lambertus A.} and Valerie Gaborieau and Chow, {Wong Ho} and David Zaridze and Vsevolod Matveev and Jan Lubinski and Joanna Trubicka and Neonila Szeszenia-Dabrowska and Jolanta Lissowska and P{\'e}ter Rudnai and Eleonora Fabianova and Alexandru Bucur and Vladimir Bencko and Lenka Foretova and Vladimir Janout and Paolo Boffetta and Colt, {Joanne S.} and Davis, {Faith G.} and Schwartz, {Kendra L.} and Banks, {Rosamonde E.} and Selby, {Peter J.} and Patricia Harnden and Hsing, {Ann W.} and Grubb, {Robert L.} and Heiner Boeing and Paolo Vineis and Franҫoise Clavel-Chapelon and Domenico Palli and Rosario Tumino and Vittorio Krogh and Salvatore Panico and Duell, {Eric J.} and Quir{\'o}s, {Jos{\'e} Ram{\'o}n} and Sanchez, {Maria Jos{\'e}} and Carmen Navarro and Eva Ardanaz and Miren Dorronsoro and Khaw, {Kay Tee} and Allen, {Naomi E.} and Bueno-de-Mesquita, {H. Bas} and Peeters, {Petra H.M.} and Dimitrios Trichopoulos and Jakob Linseisen and B{\"o}rje Ljungberg and Kim Overvad and Anne Tj{\o}nneland and Isabelle Romieu and Anush Mukeria and Oxana Shangina and Stevens, {Victoria L.} and Gapstur, {Susan M.} and Pharoah, {Paul D.} and Easton, {Douglas F.} and Inger Nj{\o}lstad and Tell, {Grethe S.} and Camilla Stoltenberg and Rajiv Kumar and Kvetoslava Koppova and Simone Benhamou and Egbert Oosterwijk and Vermeulen, {Sita H.} and Aben, {Katja K.H.} and {Van Der Marel}, {Saskia L.} and Yuanqing Ye and Wood, {Christopher G.} and Xia Pu and Mazur, {Alexander M.} and Boulygina, {Eugenia S.} and Chekanov, {Nikolai N.} and Mario Foglio and Doris Lechner and Ivo Gut and Simon Heath and H{\'e}l{\`e}ne Blanche and Skryabin, {Konstantin G.} and McKay, {James D.} and Nathaniel Rothman and Mark Lathrop and Paul Brennan and Brian Saunders and Huw Thomas and Sue Clark and Ian Tomlinson",

year = "2015",

month = feb,

day = "20",

doi = "10.1038/ejhg.2014.74",

language = "English (US)",

volume = "23",

pages = "260--263",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

AU - Cheng, Timothy H.T.

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Barclay, Ella

AU - Casey, Graham

AU - Newcomb, Polly A.

AU - Conti, David V.

AU - Schumacher, Fredrick R.

AU - Gallinger, Steve

AU - Lindor, Noralane M.

AU - Hopper, John

AU - Jenkins, Mark

AU - Hunter, David J.

AU - Kraft, Peter

AU - Jacobs, Kevin B.

AU - Cox, David G.

AU - Yeager, Meredith

AU - Hankinson, Susan E.

AU - Wacholder, Sholom

AU - Wang, Zhaoming

AU - Welch, Robert

AU - Hutchinson, Amy

AU - Wang, Junwen

AU - Yu, Kai

AU - Chatterjee, Nilanjan

AU - Orr, Nick

AU - Willett, Walter C.

AU - Colditz, Graham A.

AU - Ziegler, Regina G.

AU - Berg, Christine D.

AU - Buys, Saundra S.

AU - McCarty, Catherine A.

AU - Feigelson, Heather Spencer

AU - Calle, Eugenia E.

AU - Thun, Michael J.

AU - Hayes, Richard B.

AU - Tucker, Margaret

AU - Gerhard, Daniela S.

AU - Fraumeni, Joseph F.

AU - Hoover, Robert N.

AU - Thomas, Gilles

AU - Chanock, Stephen J.

AU - Ciampa, Julia

AU - Gonzalez-Bosquet, Jesus

AU - Berndt, Sonja

AU - Amundadottir, Laufey

AU - Diver, W. Ryan

AU - Albanes, Demetrius

AU - Virtamo, Jarmo

AU - Weinstein, Stephanie J.

AU - Cancel-Tassin, Geraldine

AU - Cussenot, Olivier

AU - Valeri, Antoine

AU - Andriole, Gerald L.

AU - Crawford, E. David

AU - Haiman, Christopher A.

AU - Henderson, Brian

AU - Kolonel, Laurence

AU - Marchand, Loic Le

AU - Siddiq, Afshan

AU - Riboli, Elio

AU - Key, Timothy J.

AU - Kaaks, Rudolf

AU - Isaacs, William

AU - Isaacs, Sarah

AU - Wiley, Kathleen E.

AU - Gronberg, Henrik

AU - Wiklund, Fredrik

AU - Stattin, Pär

AU - Xu, Jianfeng

AU - Zheng, S. Lilly

AU - Sun, Jielin

AU - Vatten, Lars J.

AU - Hveem, Kristian

AU - Kumle, Merethe

AU - Purdue, Mark P.

AU - Johansson, Mattias

AU - Zelenika, Diana

AU - Toro, Jorge R.

AU - Scelo, Ghislaine

AU - Moore, Lee E.

AU - Prokhortchouk, Egor

AU - Wu, Xifeng

AU - Kiemeney, Lambertus A.

AU - Gaborieau, Valerie

AU - Chow, Wong Ho

AU - Zaridze, David

AU - Matveev, Vsevolod

AU - Lubinski, Jan

AU - Trubicka, Joanna

AU - Szeszenia-Dabrowska, Neonila

AU - Lissowska, Jolanta

AU - Rudnai, Péter

AU - Fabianova, Eleonora

AU - Bucur, Alexandru

AU - Bencko, Vladimir

AU - Foretova, Lenka

AU - Janout, Vladimir

AU - Boffetta, Paolo

AU - Colt, Joanne S.

AU - Davis, Faith G.

AU - Schwartz, Kendra L.

AU - Banks, Rosamonde E.

AU - Selby, Peter J.

AU - Harnden, Patricia

AU - Hsing, Ann W.

AU - Grubb, Robert L.

AU - Boeing, Heiner

AU - Vineis, Paolo

AU - Clavel-Chapelon, Franҫoise

AU - Palli, Domenico

AU - Tumino, Rosario

AU - Krogh, Vittorio

AU - Panico, Salvatore

AU - Duell, Eric J.

AU - Quirós, José Ramón

AU - Sanchez, Maria José

AU - Navarro, Carmen

AU - Ardanaz, Eva

AU - Dorronsoro, Miren

AU - Khaw, Kay Tee

AU - Allen, Naomi E.

AU - Bueno-de-Mesquita, H. Bas

AU - Peeters, Petra H.M.

AU - Trichopoulos, Dimitrios

AU - Linseisen, Jakob

AU - Ljungberg, Börje

AU - Overvad, Kim

AU - Tjønneland, Anne

AU - Romieu, Isabelle

AU - Mukeria, Anush

AU - Shangina, Oxana

AU - Stevens, Victoria L.

AU - Gapstur, Susan M.

AU - Pharoah, Paul D.

AU - Easton, Douglas F.

AU - Njølstad, Inger

AU - Tell, Grethe S.

AU - Stoltenberg, Camilla

AU - Kumar, Rajiv

AU - Koppova, Kvetoslava

AU - Benhamou, Simone

AU - Oosterwijk, Egbert

AU - Vermeulen, Sita H.

AU - Aben, Katja K.H.

AU - Van Der Marel, Saskia L.

AU - Ye, Yuanqing

AU - Wood, Christopher G.

AU - Pu, Xia

AU - Mazur, Alexander M.

AU - Boulygina, Eugenia S.

AU - Chekanov, Nikolai N.

AU - Foglio, Mario

AU - Lechner, Doris

AU - Gut, Ivo

AU - Heath, Simon

AU - Blanche, Hélène

AU - Skryabin, Konstantin G.

AU - McKay, James D.

AU - Rothman, Nathaniel

AU - Lathrop, Mark

AU - Brennan, Paul

AU - Saunders, Brian

AU - Thomas, Huw

AU - Clark, Sue

AU - Tomlinson, Ian

PY - 2015/2/20

Y1 - 2015/2/20

N2 - The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10 -7 ). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

AB - The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10 -7 ). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients.

UR - http://www.scopus.com/inward/record.url?scp=84930571831&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930571831&partnerID=8YFLogxK

U2 - 10.1038/ejhg.2014.74

DO - 10.1038/ejhg.2014.74

M3 - Article

C2 - 24801760

AN - SCOPUS:84930571831

SN - 1018-4813

VL - 23

SP - 260

EP - 263

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 2

ER -

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

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