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

CELF Proteins / genetics Case-Control Studies Colorectal Neoplasms / genetics Genetic Predisposition to Disease Germ-Line Mutation Humans Pedigree
CELF4 Colorectal cancer High-risk pedigree Linkage analysis UPDB

Journal

Cancer epidemiology
ISSN: 1877-783X
Titre abrégé: Cancer Epidemiol
Pays: Netherlands
ID NLM: 101508793

Informations de publication

Date de publication:
06 2021
Historique:
received: 12 02 2021
accepted: 17 04 2021
pubmed: 1 5 2021
medline: 8 7 2021
entrez: 30 4 2021
Statut: ppublish

Résumé

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). 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. 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 ofCELF4 gene, rs568643870, was significantly associated with CRC (p = 0.004, OR = 5.0), and segregated with CRC in other members of the linked pedigree. 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 rareCELF4 intronic variant in CRC risk.

Sections du résumé

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 ofCELF4 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 rareCELF4 intronic variant in CRC risk.

Identifiants

DOI: 10.1016/j.canep.2021.101941 PMID: 33930674 PMC: PMC8158787
pubmed: 33930674
pii: S1877-7821(21)00058-8
doi: 10.1016/j.canep.2021.101941
pmc: PMC8158787
mid: NIHMS1697429
pii:
doi:

Substances chimiques

CELF Proteins 0
CELF4 protein, human 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

101941

Subventions

Organisme : CDC HHS
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002538
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800016C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800016I
Pays : United States
Organisme : NIH HHS
ID : S10 OD021644
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA042014
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201100016I
Pays : United States
Organisme : NLM NIH HHS
ID : T15 LM007124
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

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Auteurs

Craig C Teerlink (CC)

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Electronic address: craig.teerlink@utah.edu.

Jeff Stevens (J)

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. Electronic address: jstevens@genetics.utah.edu.

Rolando Hernandez (R)

Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA. Electronic address: Rolando.Hernandez@utah.edu.

Julio C Facelli (JC)

Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; Center for Clinical and Translational Science, University of Utah School of Medicine, Salt Lake City, UT 84108, USA. Electronic address: Julio.Facelli@utah.edu.

Lisa A Cannon-Albright (LA)

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA; Huntsman Cancer Institute, Salt Lake City, UT 84112, USA. Electronic address: lisa.albright@utah.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Protéines de liaison à l'ARN › Protéines à motif de reconnaissance de l'ARN › Protéines CELF › An intronic variant in the CELF4 gene is...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › An intronic variant in the CELF4 gene is...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › An intronic variant in the CELF4 gene is...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › An intronic variant in the CELF4 gene is...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation germinale › An intronic variant in the CELF4 gene is...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › An intronic variant in the CELF4 gene is...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Pedigree › An intronic variant in the CELF4 gene is...