An intronic variant in the CELF4 gene is associated with risk for colorectal cancer

Details

• Alternative Title:
  Cancer Epidemiol
• Personal Author:
  Teerlink, Craig C. ; Stevens, Jeff ; Hernandez, Rolando ; Facelli, Julio C. ; Cannon-Albright, Lisa A.
• Description:
  Background:
  
  Germline predisposition variants associated with colorectal cancer (CRC) have been identified but all are not yet identified. We sought to identify the responsible predisposition germline variant in an extended high-risk CRC pedigree that exhibited evidence of linkage to the 18q12.2 region (TLOD = +2.81).
  
  Methods:
  
  DNA from two distantly related carriers of the hypothesized predisposition haplotype on 18q12.2 was sequenced to identify candidate variants. The candidate rare variants shared by the related sequenced subjects were screened in 3,094 CRC cases and 5x population-matched controls from UKBiobank to test for association. Further segregation of the variant was tested via Taqman assay in other sampled individuals in the pedigree.
  
  Results:
  
  Analysis of whole genome sequence data for the two related hypothesized predisposition haplotype carriers, restricted to the shared haplotype boundaries, identified multiple (n=6) rare candidate non-coding variants that were tested for association with CRC risk in UKBiobank. A rare intronic variant of CELF4 gene, rs568643870, was significantly associated with CRC (p=0.004, OR=5.0), and segregated with CRC in other members of the linked pedigree.
  
  Conclusion:
  
  Evidence of segregation in a high-risk pedigree, case-control association in an external dataset, and identification of additional CRC-affected carriers in the linked pedigree support a role for a rare CELF4 intronic variant in CRC risk.
  
  
• Subjects:
  Case-Control Studies CELF Proteins Colorectal Neoplasms Genetic Predisposition To Disease Germ-Line Mutation Humans Pedigree
• Keywords:
  Buprenorphine CELF4 Colorectal Cancer High-risk Pedigree Linkage Analysis Methadone Mortality Naltrexone Treatment UPDB
• Source:
  Cancer Epidemiol. 72:101941
• Pubmed ID:
  33930674
• Pubmed Central ID:
  PMC8158787
• Document Type:
  Journal Article
• Funding:
  CC/CDC HHSUnited States/ ; UL1 TR002538/TR/NCATS NIH HHSUnited States/ ; S10 OD021644/OD/NIH HHSUnited States/ ; P30 CA042014/CA/NCI NIH HHSUnited States/ ; HHSN261201100016I/CA/NCI NIH HHSUnited States/ ; T15 LM007124/LM/NLM NIH HHSUnited States/
• Volume:
  72
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:70a891dc7e527c5895f1584dddce60ebc17dfd3b0d462896c807baf025e35ebe022aa7406ebb230aa4485c60a467d831834ce3f4acb9e42aac3bf0acb81025dc
• Download URL:
  https://stacks.cdc.gov/view/cdc/117905/cdc_117905_DS1.pdf
• File Type:
  [PDF - 971.43 KB ]