Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Details

• Alternative Title:
  Cancer Epidemiol Biomarkers Prev
• Personal Author:
  Win, Aung Ko ; Jenkins, Mark A. ; Dowty, James G. ; Antoniou, Antonis C. ; Lee, Andrew ; Giles, Graham G. ; Buchanan, Daniel D. ; Clendenning, Mark ; Rosty, Christophe ; Ahnen, Dennis J. ; Thibodeau, Stephen N. ; Casey, Graham ; Gallinger, Steven ; Le Marchand, Loïc ; Haile, Robert W. ; Potter, John D. ; Zheng, Yingye ; Lindor, Noralane M. ; Newcomb, Polly A. ; Hopper, John L. ; MacInnis, Robert J.
• Description:
  Background
  
  While high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) 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 USA, Canada and Australia and screened probands for mutations in mismatch repair genes and MUTYH. 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 and hazard ratio 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 1946, MSH2= 1 in 2841, MSH6= 1 in 758, PMS2= 1 in 714), 1 in 45 carry mutations in MUTYH, 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 30–50% 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).
  
  Conclusion
  
  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.
  
  
• Subjects:
  Adult Aged Colorectal Neoplasms DNA Glycosylases DNA Mismatch Repair Female Genetic Predisposition To Disease Humans Male Middle Aged Multifactorial Inheritance Mutation MutL Protein Homolog 1 Penetrance Population Surveillance Prevalence Risk Factors

  More +
• Keywords:
  Colorectal Cancer Familial Aggregation Family History Polygenes Risk Prediction
• Source:
  Cancer Epidemiol Biomarkers Prev. 26(3):404-412
• Pubmed ID:
  27799157
• Pubmed Central ID:
  PMC5336409
• Document Type:
  Journal Article
• Funding:
  U01 CA074799/CA/NCI NIH HHSUnited States/ ; U24 CA074794/CA/NCI NIH HHSUnited States/ ; 20861/CRUK_/Cancer Research UKUnited Kingdom/ ; 11174/CRUK_/Cancer Research UKUnited Kingdom/ ; U01 CA167551/CA/NCI NIH HHSUnited States/ ; HHSN261201300012I/CA/NCI NIH HHSUnited States/ ; N01PC35142/CA/NCI NIH HHSUnited States/ ; P30 CA015083/CA/NCI NIH HHSUnited States/ ; U01 CA097735/CA/NCI NIH HHSUnited States/ ; U58 DP003862/DP/NCCDPHP CDC HHSUnited States/ ; U01 CA074783/CA/NCI NIH HHSUnited States/ ; U24 CA074799/CA/NCI NIH HHSUnited States/ ; U24 CA074800/CA/NCI NIH HHSUnited States/ ; U01 CA074800/CA/NCI NIH HHSUnited States/ ; U24 CA074783/CA/NCI NIH HHSUnited States/ ; N01 CN067009/CN/NCI NIH HHSUnited States/ ; R01 CA170122/CA/NCI NIH HHSUnited States/ ; U24 CA097735/CA/NCI NIH HHSUnited States/ ; U01 CA074794/CA/NCI NIH HHSUnited States/ ; K05 CA152715/CA/NCI NIH HHSUnited States/ ; UM1 CA167551/CA/NCI NIH HHSUnited States/
• Volume:
  26
• Issue:
  3
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:7da7e18c590febcbaa7572b3a6a07bb9a73f14d74007f20dd4752f413e21d40d00f9d16cef85c8b8add4aa25df5c423c54540b26f19ba7b1d3d0b45c47f9ddef
• Download URL:
  https://stacks.cdc.gov/view/cdc/44525/cdc_44525_DS1.pdf
• File Type:
  [PDF - 398.65 KB ]