2.50
Hdl Handle:
http://hdl.handle.net/2336/65453
Title:
The BARD1 Cys557Ser variant and breast cancer risk in Iceland.
Authors:
Stacey, Simon N; Sulem, Patrick; Johannsson, Oskar T; Helgason, Agnar; Gudmundsson, Julius; Kostic, Jelena P; Kristjansson, Kristleifur; Jonsdottir, Thora; Sigurdsson, Helgi; Hrafnkelsson, Jon; Johannsson, Jakob; Sveinsson, Thorarinn; Myrdal, Gardar; Grimsson, Hlynur Niels; Bergthorsson, Jon T; Amundadottir, Laufey T; Gulcher, Jeffrey R; Thorsteinsdottir, Unnur; Kong, Augustine; Stefansson, Kari
Citation:
PLoS Med. 2006, 3(7):e217
Issue Date:
1-Jul-2006
Abstract:
BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://dx.doi.org/10.1371%2Fjournal.pmed.0030217

Full metadata record

DC FieldValue Language
dc.contributor.authorStacey, Simon N-
dc.contributor.authorSulem, Patrick-
dc.contributor.authorJohannsson, Oskar T-
dc.contributor.authorHelgason, Agnar-
dc.contributor.authorGudmundsson, Julius-
dc.contributor.authorKostic, Jelena P-
dc.contributor.authorKristjansson, Kristleifur-
dc.contributor.authorJonsdottir, Thora-
dc.contributor.authorSigurdsson, Helgi-
dc.contributor.authorHrafnkelsson, Jon-
dc.contributor.authorJohannsson, Jakob-
dc.contributor.authorSveinsson, Thorarinn-
dc.contributor.authorMyrdal, Gardar-
dc.contributor.authorGrimsson, Hlynur Niels-
dc.contributor.authorBergthorsson, Jon T-
dc.contributor.authorAmundadottir, Laufey T-
dc.contributor.authorGulcher, Jeffrey R-
dc.contributor.authorThorsteinsdottir, Unnur-
dc.contributor.authorKong, Augustine-
dc.contributor.authorStefansson, Kari-
dc.date.accessioned2009-04-20T09:54:46Z-
dc.date.available2009-04-20T09:54:46Z-
dc.date.issued2006-07-01-
dc.date.submitted2009-04-20-
dc.identifier.citationPLoS Med. 2006, 3(7):e217en
dc.identifier.issn1549-1676-
dc.identifier.pmid16768547-
dc.identifier.doi10.1371/journal.pmed.0030217-
dc.identifier.urihttp://hdl.handle.net/2336/65453-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractBACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relation.urlhttp://dx.doi.org/10.1371%2Fjournal.pmed.0030217en
dc.subject.meshAdulten
dc.subject.meshAge of Onseten
dc.subject.meshAgeden
dc.subject.meshAllelesen
dc.subject.meshAmino Acid Substitutionen
dc.subject.meshBreast Neoplasmsen
dc.subject.meshCarcinoma in Situen
dc.subject.meshCarcinoma, Ductal, Breasten
dc.subject.meshCarcinoma, Intraductal, Noninfiltratingen
dc.subject.meshCarcinoma, Lobularen
dc.subject.meshCarcinoma, Medullaryen
dc.subject.meshCase-Control Studiesen
dc.subject.meshCluster Analysisen
dc.subject.meshCohort Studiesen
dc.subject.meshFemaleen
dc.subject.meshFounder Effecten
dc.subject.meshGene Frequencyen
dc.subject.meshGenes, BRCA2en
dc.subject.meshGenetic Predisposition to Diseaseen
dc.subject.meshGenotypeen
dc.subject.meshHaplotypesen
dc.subject.meshHumansen
dc.subject.meshIcelanden
dc.subject.meshMiddle Ageden
dc.subject.meshMutation, Missenseen
dc.subject.meshNeoplastic Syndromes, Hereditaryen
dc.subject.meshOdds Ratioen
dc.subject.meshPoint Mutationen
dc.subject.meshPolymorphism, Single Nucleotideen
dc.subject.meshRisken
dc.subject.meshSequence Deletionen
dc.subject.meshTumor Suppressor Proteinsen
dc.subject.meshUbiquitin-Protein Ligasesen
dc.titleThe BARD1 Cys557Ser variant and breast cancer risk in Iceland.en
dc.typeArticleen
dc.contributor.departmentdeCODE Genetics, Reykjavik, Iceland. simon.stacey@decode.isen
dc.identifier.journalPLoS medicineen

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