PURPOSE: Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC. PATIENTS AND METHODS: MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived. RESULTS: CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest. CONCLUSION: The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles.
PURPOSE: Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC. PATIENTS AND METHODS: MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived. RESULTS: CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest. CONCLUSION: The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles.
Authors: Rebecca E Graff; Sören Möller; Michael N Passarelli; John S Witte; Axel Skytthe; Kaare Christensen; Qihua Tan; Hans-Olov Adami; Kamila Czene; Jennifer R Harris; Eero Pukkala; Jaakko Kaprio; Edward L Giovannucci; Lorelei A Mucci; Jacob B Hjelmborg Journal: Clin Gastroenterol Hepatol Date: 2017-01-24 Impact factor: 11.382
Authors: Isabel de la Torre; Francisco Javier Díaz; Míriam Antón; Esteban Barragán; Joel Rodrigues; Celina Pires Journal: J Med Syst Date: 2011-05-06 Impact factor: 4.460
Authors: Malcolm G Dunlop; Sara E Dobbins; Susan Mary Farrington; Angela M Jones; Claire Palles; Nicola Whiffin; Albert Tenesa; Sarah Spain; Peter Broderick; Li-Yin Ooi; Enric Domingo; Claire Smillie; Marc Henrion; Matthew Frampton; Lynn Martin; Graeme Grimes; Maggie Gorman; Colin Semple; Yusanne P Ma; Ella Barclay; James Prendergast; Jean-Baptiste Cazier; Bianca Olver; Steven Penegar; Steven Lubbe; Ian Chander; Luis G Carvajal-Carmona; Stephane Ballereau; Amy Lloyd; Jayaram Vijayakrishnan; Lina Zgaga; Igor Rudan; Evropi Theodoratou; John M Starr; Ian Deary; Iva Kirac; Dujo Kovacević; Lauri A Aaltonen; Laura Renkonen-Sinisalo; Jukka-Pekka Mecklin; Koichi Matsuda; Yusuke Nakamura; Yukinori Okada; Steven Gallinger; David J Duggan; David Conti; Polly Newcomb; John Hopper; Mark A Jenkins; Fredrick Schumacher; Graham Casey; Douglas Easton; Mitul Shah; Paul Pharoah; Annika Lindblom; Tao Liu; Christopher G Smith; Hannah West; Jeremy P Cheadle; Rachel Midgley; David J Kerr; Harry Campbell; Ian P Tomlinson; Richard S Houlston Journal: Nat Genet Date: 2012-05-27 Impact factor: 38.330
Authors: Kevin J Monahan; Nicola Bradshaw; Sunil Dolwani; Bianca Desouza; Malcolm G Dunlop; James E East; Mohammad Ilyas; Asha Kaur; Fiona Lalloo; Andrew Latchford; Matthew D Rutter; Ian Tomlinson; Huw J W Thomas; James Hill Journal: Gut Date: 2019-11-28 Impact factor: 23.059
Authors: Nicola Whiffin; Sara E Dobbins; Fay J Hosking; Claire Palles; Albert Tenesa; Yufei Wang; Susan M Farrington; Angela M Jones; Peter Broderick; Harry Campbell; Polly A Newcomb; Graham Casey; David V Conti; Fred Schumacher; Steve Gallinger; Noralane M Lindor; John Hopper; Mark Jenkins; Malcolm G Dunlop; Ian P Tomlinson; Richard S Houlston Journal: Hum Mol Genet Date: 2013-07-30 Impact factor: 6.150