Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
Date
2016-11-10Author
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 recordAbstract
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 (POT1) 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 ACD (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 POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development.
Collections
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
Publisher
AMER SOC HEMATOLOGY