title: Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
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 inACD(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, thePOT1p.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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Ben
authors.initials: B
authors.lastname: Kinnersley
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Chubb
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Law
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Litchfield
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jayne
authors.affiliation: Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
authors.forename: Martin J S
authors.initials: MJS
authors.lastname: Dyer
authors.affiliation: Department of Haemato-Oncology, The Royal Marsden National Health Service Foundation Trust, Sutton, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Dearden
authors.affiliation: Department of Haematology, Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom; and.
authors.forename: George A
authors.initials: GA
authors.lastname: Follows
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.|Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000595:Amino Acid Sequence; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D000089804:Shelterin Complex; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C440849:POT1 protein, human; D022821:RNA Splice Sites; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins