title: Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.
abstract: Background:Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes andMUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.Methods:We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes andMUTYHWe conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.Results:We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1= 1 in 1,946,MSH2= 1 in 2,841,MSH6= 1 in 758,PMS2= 1 in 714), 1 in 45 carry mutations inMUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).Conclusions:Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.Impact:Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.Cancer Epidemiol Biomarkers Prev; 26(3); 404-12. ©2016 AACR.
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: Aung Ko
authors: AK
authors: Win
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: Mark A
authors: MA
authors: Jenkins
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: James G
authors: JG
authors: Dowty
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors: Antonis C
authors: AC
authors: Antoniou
authors: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors: Andrew
authors: A
authors: Lee
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
authors: Graham G
authors: GG
authors: Giles
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.|Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Daniel D
authors: DD
authors: Buchanan
authors: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors: Mark
authors: M
authors: Clendenning
authors: Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors: Christophe
authors: C
authors: Rosty
authors: University of Colorado School of Medicine, Denver, Colorado.
authors: Dennis J
authors: DJ
authors: Ahnen
authors: Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Stephen N
authors: SN
authors: Thibodeau
authors: Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
authors: Graham
authors: G
authors: Casey
authors: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors: Steven
authors: S
authors: Gallinger
authors: University of Hawaii Cancer Center, Honolulu, Hawaii.
authors: Loïc
authors: L
authors: Le Marchand
authors: Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, California.
authors: Robert W
authors: RW
authors: Haile
authors: School of Public Health, University of Washington, Seattle, Washington.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors: John D
authors: JD
authors: Potter
authors: School of Public Health, University of Washington, Seattle, Washington.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Yingye
authors: Y
authors: Zheng
authors: Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona.
authors: Noralane M
authors: NM
authors: Lindor
authors: School of Public Health, University of Washington, Seattle, Washington.|Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors: Polly A
authors: PA
authors: Newcomb
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors: John L
authors: JL
authors: Hopper
authors: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia. robert.macinnis@cancervic.org.au.|Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
authors: Robert J
authors: RJ
authors: MacInnis
mesh_terms: D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D000070957:MutL Protein Homolog 1 / Q000235:genetics; D009154:Mutation; D019683:Penetrance; D011159:Population Surveillance; D015995:Prevalence; D012307:Risk Factors
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000070957:MutL Protein Homolog 1