Publications Repository

Publications Repository

View Item 
  •   Home
  • ICR Divisions
  • Genetics and Epidemiology
  • View Item
  • Home
  • ICR Divisions
  • Genetics and Epidemiology
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

Thumbnail
View/Open
Accepted version (268.3Kb)
Supporting information (1.389Mb)
Publication Date
2016-11
ICR Author
Speedy, Helen
Litchfield, Kevin
Houlston, Richard
Author
Speedy, HE
Kinnersley, B
Chubb, D
Broderick, P
Law, PJ
Litchfield, K
Jayne, S
Dyer, MJS
Dearden, C
Follows, GA
Catovsky, D
Houlston, RS
Type
Journal Article
Metadata
Show full item record
Abstract
Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (<i>POT1</i>) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in <i>ACD</i> (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the <i>POT1</i> p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (<i>P</i> = .009). This study further highlights telomere dysregulation as a key process in CLL development.
URL
https://repository.icr.ac.uk/handle/internal/44
Collections
  • Genetics and Epidemiology
  • Molecular Pathology
Licenseref URL
https://creativecommons.org/licenses/by/4.0
Version of record
10.1182/blood-2016-01-695692
Subject
Humans
Telomere-Binding Proteins
RNA Splice Sites
Pedigree
Amino Acid Sequence
Germ-Line Mutation
Female
Male
Leukemia, Lymphocytic, Chronic, B-Cell
Telomere Homeostasis
Research team
Cancer Genomics
Molecular & Population Genetics
Language
eng
Date accepted
2016-08-08
License start date
2016-11
Citation
Blood, 2016, 128 (19), pp. 2319 - 2326

Browse

All of ICR repositoryICR DivisionsIssue dateAuthorsTitlesSubjectsThis collectionIssue dateAuthorsTitlesSubjects

Statistics

Most popular itemsStatistics by countryMost popular authors
  • Login
  • Registered office: The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP
    A Charity, Not for Profit. Company Limited by Guarantee.
    Registered in England No. 534147. VAT Registration No. GB 849 0581 02.