dc.contributor.author | Speedy, HE | |
dc.contributor.author | Kinnersley, B | |
dc.contributor.author | Chubb, D | |
dc.contributor.author | Broderick, P | |
dc.contributor.author | Law, PJ | |
dc.contributor.author | Litchfield, K | |
dc.contributor.author | Jayne, S | |
dc.contributor.author | Dyer, MJS | |
dc.contributor.author | Dearden, C | |
dc.contributor.author | Follows, GA | |
dc.contributor.author | Catovsky, D | |
dc.contributor.author | Houlston, RS | |
dc.date.accessioned | 2016-08-16T11:40:26Z | |
dc.date.issued | 2016-11-10 | |
dc.identifier.citation | Blood, 2016, 128 (19), pp. 2319 - 2326 | |
dc.identifier.issn | 0006-4971 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/44 | |
dc.identifier.eissn | 1528-0020 | |
dc.identifier.doi | 10.1182/blood-2016-01-695692 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 2319 - 2326 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC HEMATOLOGY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Telomere-Binding Proteins | |
dc.subject | RNA Splice Sites | |
dc.subject | Pedigree | |
dc.subject | Amino Acid Sequence | |
dc.subject | Germ-Line Mutation | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Leukemia, Lymphocytic, Chronic, B-Cell | |
dc.subject | Telomere Homeostasis | |
dc.title | Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-08-08 | |
rioxxterms.versionofrecord | 10.1182/blood-2016-01-695692 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-11 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Blood | |
pubs.issue | 19 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Cancer Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics | |
pubs.publication-status | Published | |
pubs.volume | 128 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Cancer Genomics | |
icr.researchteam | Molecular & Population Genetics | |
dc.contributor.icrauthor | Speedy, Helen | |
dc.contributor.icrauthor | Kinnersley, Benjamin | |
dc.contributor.icrauthor | Litchfield, Kevin | |
dc.contributor.icrauthor | Houlston, Richard | |