Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
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Authors
Speedy, HE
Kinnersley, B
Chubb, D
Broderick, P
Law, PJ
Litchfield, K
Jayne, S
Dyer, MJS
Dearden, C
Follows, GA
Catovsky, D
Houlston, RS
Kinnersley, B
Chubb, D
Broderick, P
Law, PJ
Litchfield, K
Jayne, S
Dyer, MJS
Dearden, C
Follows, GA
Catovsky, D
Houlston, RS
Document Type
Journal Article
Date
2016-11-10
Date Accepted
2016-08-08
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 (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.
Citation
Blood, 2016, 128 (19), pp. 2319 - 2326
Source Title
Publisher
ELSEVIER
ISSN
0006-4971
eISSN
1528-0020
Collections
Research Team
Cancer Genomics
Molecular & Population Genetics
Molecular & Population Genetics