BACKGROUND: Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. METHODS: We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). RESULTS: We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. CONCLUSIONS: These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
BACKGROUND: Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. METHODS: We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). RESULTS: We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. CONCLUSIONS: These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
Authors: B Rivera; S González; E Sánchez-Tomé; I Blanco; F Mercadillo; R Letón; J Benítez; M Robledo; G Capellá; M Urioste Journal: Ann Oncol Date: 2010-10-05 Impact factor: 32.976
Authors: Bente A Talseth-Palmer; Ingvild S Brenne; Katie A Ashton; Tiffany-Jane Evans; Mary McPhillips; Claire Groombridge; Janina Suchy; Grzegorz Kurzawski; Allan Spigelman; Jan Lubinski; Rodney J Scott Journal: J Med Genet Date: 2010-11-19 Impact factor: 6.318
Authors: Peter Broderick; Luis Carvajal-Carmona; Alan M Pittman; Emily Webb; Kimberley Howarth; Andrew Rowan; Steven Lubbe; Sarah Spain; Kate Sullivan; Sarah Fielding; Emma Jaeger; Jayaram Vijayakrishnan; Zoe Kemp; Maggie Gorman; Ian Chandler; Elli Papaemmanuil; Steven Penegar; Wendy Wood; Gabrielle Sellick; Mobshra Qureshi; Ana Teixeira; Enric Domingo; Ella Barclay; Lynn Martin; Oliver Sieber; David Kerr; Richard Gray; Julian Peto; Jean-Baptiste Cazier; Ian Tomlinson; Richard S Houlston Journal: Nat Genet Date: 2007-10-14 Impact factor: 38.330
Authors: C Mongin; F Coulet; J H Lefevre; C Colas; M Svrcek; M Eyries; Y Lahely; J-F Fléjou; F Soubrier; Y Parc Journal: Clin Genet Date: 2011-05-04 Impact factor: 4.438
Authors: M Nielsen; F J Hes; F M Nagengast; M M Weiss; E M Mathus-Vliegen; H Morreau; M H Breuning; J T Wijnen; C M J Tops; H F A Vasen Journal: Clin Genet Date: 2007-05 Impact factor: 4.438
Authors: Richard S Houlston; Emily Webb; Peter Broderick; Alan M Pittman; Maria Chiara Di Bernardo; Steven Lubbe; Ian Chandler; Jayaram Vijayakrishnan; Kate Sullivan; Steven Penegar; Luis Carvajal-Carmona; Kimberley Howarth; Emma Jaeger; Sarah L Spain; Axel Walther; Ella Barclay; Lynn Martin; Maggie Gorman; Enric Domingo; Ana S Teixeira; David Kerr; Jean-Baptiste Cazier; Iina Niittymäki; Sari Tuupanen; Auli Karhu; Lauri A Aaltonen; Ian P M Tomlinson; Susan M Farrington; Albert Tenesa; James G D Prendergast; Rebecca A Barnetson; Roseanne Cetnarskyj; Mary E Porteous; Paul D P Pharoah; Thibaud Koessler; Jochen Hampe; Stephan Buch; Clemens Schafmayer; Jurgen Tepel; Stefan Schreiber; Henry Völzke; Jenny Chang-Claude; Michael Hoffmeister; Hermann Brenner; Brent W Zanke; Alexandre Montpetit; Thomas J Hudson; Steven Gallinger; Harry Campbell; Malcolm G Dunlop Journal: Nat Genet Date: 2008-11-16 Impact factor: 38.330
Authors: Emma Jaeger; Emily Webb; Kimberley Howarth; Luis Carvajal-Carmona; Andrew Rowan; Peter Broderick; Axel Walther; Sarah Spain; Alan Pittman; Zoe Kemp; Kate Sullivan; Karl Heinimann; Steven Lubbe; Enric Domingo; Ella Barclay; Lynn Martin; Maggie Gorman; Ian Chandler; Jayaram Vijayakrishnan; Wendy Wood; Elli Papaemmanuil; Steven Penegar; Mobshra Qureshi; Susan Farrington; Albert Tenesa; Jean-Baptiste Cazier; David Kerr; Richard Gray; Julian Peto; Malcolm Dunlop; Harry Campbell; Huw Thomas; Richard Houlston; Ian Tomlinson Journal: Nat Genet Date: 2007-12-16 Impact factor: 38.330
Authors: C Thirlwell; K M Howarth; S Segditsas; G Guerra; H J W Thomas; R K S Phillips; I C Talbot; M Gorman; M R Novelli; O M Sieber; I P M Tomlinson Journal: Br J Cancer Date: 2007-05-15 Impact factor: 7.640
Authors: Elisabeth A Rosenthal; Brian H Shirts; Laura M Amendola; Martha Horike-Pyne; Peggy D Robertson; Fuki M Hisama; Robin L Bennett; Michael O Dorschner; Deborah A Nickerson; Ian B Stanaway; Rami Nassir; Kathy T Vickers; Christopher Li; William M Grady; Ulrike Peters; Gail P Jarvik Journal: Hum Genet Date: 2018-09-28 Impact factor: 4.132
Authors: Ronja Adam; Isabel Spier; Bixiao Zhao; Michael Kloth; Jonathan Marquez; Inga Hinrichsen; Jutta Kirfel; Aylar Tafazzoli; Sukanya Horpaopan; Siegfried Uhlhaas; Dietlinde Stienen; Nicolaus Friedrichs; Janine Altmüller; Andreas Laner; Stefanie Holzapfel; Sophia Peters; Katrin Kayser; Holger Thiele; Elke Holinski-Feder; Giancarlo Marra; Glen Kristiansen; Markus M Nöthen; Reinhard Büttner; Gabriela Möslein; Regina C Betz; Angela Brieger; Richard P Lifton; Stefan Aretz Journal: Am J Hum Genet Date: 2016-07-28 Impact factor: 11.025
Authors: Diantha Terlouw; Manon Suerink; Sunny S Singh; Hans J J P Gille; Frederik J Hes; Alexandra M J Langers; Hans Morreau; Hans F A Vasen; Yvonne J Vos; Tom van Wezel; Carli M Tops; Sanne W Ten Broeke; Maartje Nielsen Journal: Eur J Hum Genet Date: 2019-09-16 Impact factor: 4.246
Authors: Fadwa A Elsayed; C Marleen Kets; Dina Ruano; Brendy van den Akker; Arjen R Mensenkamp; Melanie Schrumpf; Maartje Nielsen; Juul T Wijnen; Carli M Tops; Marjolijn J Ligtenberg; Hans F A Vasen; Frederik J Hes; Hans Morreau; Tom van Wezel Journal: Eur J Hum Genet Date: 2014-11-05 Impact factor: 4.246
Authors: Amy L Masson; Bente A Talseth-Palmer; Tiffany-Jane Evans; Patrick McElduff; Allan D Spigelman; Garry N Hannan; Rodney J Scott Journal: Meta Gene Date: 2015-12-24
Authors: Timothy H T Cheng; Maggie Gorman; Lynn Martin; Ella Barclay; Graham Casey; Brian Saunders; Huw Thomas; Sue Clark; Ian Tomlinson Journal: Eur J Hum Genet Date: 2014-05-07 Impact factor: 4.246
Authors: Z Ghorbanoghli; M H Nieuwenhuis; J J Houwing-Duistermaat; S Jagmohan-Changur; F J Hes; C M Tops; A Wagner; C M Aalfs; S Verhoef; E B Gómez García; R H Sijmons; F H Menko; T G Letteboer; N Hoogerbrugge; T van Wezel; H F A Vasen; J T Wijnen Journal: Fam Cancer Date: 2016-10 Impact factor: 2.375