Dong Hang1,2, Amit D Joshi3, Xiaosheng He3,4, Andrew T Chan3,5,6, Manol Jovani3, Manish K Gala3, Shuji Ogino6,7,8,9, Peter Kraft9,10, Constance Turman9,11, Ulrike Peters12,13, Stephanie A Bien12, Yi Lin12, Zhibin Hu1, Hongbing Shen1, Kana Wu2, Edward L Giovannucci2,5,9, Mingyang Song2,3,9. 1. Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, China. 2. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 3. Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. 4. Department of Colorectal Surgery, Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 5. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 6. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. 7. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. 8. Program in MPE Molecular Pathological Epidemiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. 9. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 10. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 11. Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 12. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 13. Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
Abstract
BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.
BACKGROUND: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. METHODS: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. RESULTS: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). CONCLUSIONS: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.
Authors: Ian P M Tomlinson; Emily Webb; Luis Carvajal-Carmona; Peter Broderick; Kimberley Howarth; Alan M Pittman; Sarah Spain; Steven Lubbe; Axel Walther; Kate Sullivan; Emma Jaeger; Sarah Fielding; Andrew Rowan; Jayaram Vijayakrishnan; Enric Domingo; Ian Chandler; Zoe Kemp; Mobshra Qureshi; Susan M Farrington; Albert Tenesa; James G D Prendergast; Rebecca A Barnetson; Steven Penegar; Ella Barclay; Wendy Wood; Lynn Martin; Maggie Gorman; Huw Thomas; Julian Peto; D Timothy Bishop; Richard Gray; Eamonn R Maher; Anneke Lucassen; David Kerr; D Gareth R Evans; Clemens Schafmayer; Stephan Buch; Henry Völzke; Jochen Hampe; Stefan Schreiber; Ulrich John; Thibaud Koessler; Paul Pharoah; 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 Aaltonen; Jean-Baptiste Cazier; Harry Campbell; Malcolm G Dunlop; Richard S Houlston Journal: Nat Genet Date: 2008-03-30 Impact factor: 38.330
Authors: D J Hunter; S E Hankinson; H Hough; D M Gertig; M Garcia-Closas; D Spiegelman; J E Manson; G A Colditz; W C Willett; F E Speizer; K Kelsey Journal: Carcinogenesis Date: 1997-11 Impact factor: 4.944
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