{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Win AK"],"funding":["CCR NIH HHS","Cancer Research UK","NCCDPHP CDC HHS","NCI NIH HHS"],"pagination":["404-412"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5336409"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["26(3)"],"pubmed_abstract":["<b>Background:</b> Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and <i>MUTYH</i>) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.<b>Methods:</b> 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 and <i>MUTYH</i> We 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.<b>Results:</b> We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (<i>MLH1</i> = 1 in 1,946, <i>MSH2</i> = 1 in 2,841, <i>MSH6</i> = 1 in 758, <i>PMS2</i> = 1 in 714), 1 in 45 carry mutations in <i>MUTYH</i>, 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).<b>Conclusions:</b> Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.<b>Impact:</b> Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. <i>Cancer Epidemiol Biomarkers Prev; 26(3); 404-12. ©2016 AACR</i>."],"journal":["Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology"],"pubmed_title":["Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer."],"pmcid":["PMC5336409"],"funding_grant_id":["U24 CA074783","U01 CA074783","K05 CA152715","HHSN261201300012I","HHSN261201000121C","HHSN261201000034C","U58 DP003862","UM1 CA167551","U01 CA074800","U24 CA074800","20861","HHSN261201300011C","U24 CA074794","HHSN261201300021C","11174","U01 CA074794","HHSN261201000035I","N01 CN067009","HHSN261201000035C","U01 CA097735","R01 CA170122","P30 CA015083","N01PC35142","U01 CA074799","U24 CA074799","U24 CA097735"],"pubmed_authors":["Win AK","Dowty JG","Haile RW","Zheng Y","Potter JD","Lindor NM","Antoniou AC","Clendenning M","Rosty C","Le Marchand L","Lee A","Hopper JL","Gallinger S","Jenkins MA","Thibodeau SN","Giles GG","Casey G","Buchanan DD","Newcomb PA","Ahnen DJ","MacInnis RJ"],"additional_accession":[]},"is_claimable":false,"name":"Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.","description":"<b>Background:</b> Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and <i>MUTYH</i>) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.<b>Methods:</b> 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 and <i>MUTYH</i> We 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.<b>Results:</b> We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (<i>MLH1</i> = 1 in 1,946, <i>MSH2</i> = 1 in 2,841, <i>MSH6</i> = 1 in 758, <i>PMS2</i> = 1 in 714), 1 in 45 carry mutations in <i>MUTYH</i>, 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).<b>Conclusions:</b> Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.<b>Impact:</b> Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. <i>Cancer Epidemiol Biomarkers Prev; 26(3); 404-12. ©2016 AACR</i>.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Mar","modification":"2024-11-12T11:04:15.892Z","creation":"2019-03-27T02:37:48Z"},"accession":"S-EPMC5336409","cross_references":{"pubmed":["27799157"],"doi":["10.1158/1055-9965.epi-16-0693","10.1158/1055-9965.EPI-16-0693"]}}