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dc.contributor.authorSpeedy, HE
dc.contributor.authorKinnersley, B
dc.contributor.authorChubb, D
dc.contributor.authorBroderick, P
dc.contributor.authorLaw, PJ
dc.contributor.authorLitchfield, K
dc.contributor.authorJayne, S
dc.contributor.authorDyer, MJS
dc.contributor.authorDearden, C
dc.contributor.authorFollows, GA
dc.contributor.authorCatovsky, D
dc.contributor.authorHoulston, RS
dc.date.accessioned2016-08-16T11:40:26Z
dc.date.issued2016-11
dc.identifier.citationBlood, 2016, 128 (19), pp. 2319 - 2326
dc.identifier.issn0006-4971
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/44
dc.identifier.eissn1528-0020
dc.identifier.doi10.1182/blood-2016-01-695692
dc.description.abstractChronic 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.
dc.formatPrint-Electronic
dc.format.extent2319 - 2326
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectTelomere-Binding Proteins
dc.subjectRNA Splice Sites
dc.subjectPedigree
dc.subjectAmino Acid Sequence
dc.subjectGerm-Line Mutation
dc.subjectFemale
dc.subjectMale
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cell
dc.subjectTelomere Homeostasis
dc.titleGerm line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.
dc.typeJournal Article
dcterms.dateAccepted2016-08-08
rioxxterms.versionofrecord10.1182/blood-2016-01-695692
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfBlood
pubs.issue19
pubs.notesNo 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-statusPublished
pubs.volume128en_US
pubs.embargo.termsNo embargo
icr.researchteamCancer Genomicsen_US
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorSpeedy, Helenen
dc.contributor.icrauthorLitchfield, Kevinen
dc.contributor.icrauthorHoulston, Richarden


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