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 journalArticlepeer-review

9 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 languageEnglish (US)
Pages (from-to)260-263
Number of pages4
JournalEuropean Journal of Human Genetics
Volume23
Issue number2
DOIs
StatePublished - Feb 20 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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