RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability.

2.50
Hdl Handle:
http://hdl.handle.net/2336/21772
Title:
RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability.
Authors:
Heikkinen, Katri; Rapakko, Katrin; Karppinen, Sanna-Maria; Erkko, Hannele; Knuutila, Sakari; Lundán, Tuija; Mannermaa, Arto; Børresen-Dale, Anne-Lise; Borg, Ake; Barkardottir, Rosa B; Petrini, John; Winqvist, Robert
Citation:
Carcinogenesis 2006, 27(8):1593-9
Issue Date:
1-Aug-2006
Abstract:
The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://carcin.oxfordjournals.org/cgi/content/abstract/27/8/1593

Full metadata record

DC FieldValue Language
dc.contributor.authorHeikkinen, Katri-
dc.contributor.authorRapakko, Katrin-
dc.contributor.authorKarppinen, Sanna-Maria-
dc.contributor.authorErkko, Hannele-
dc.contributor.authorKnuutila, Sakari-
dc.contributor.authorLundán, Tuija-
dc.contributor.authorMannermaa, Arto-
dc.contributor.authorBørresen-Dale, Anne-Lise-
dc.contributor.authorBorg, Ake-
dc.contributor.authorBarkardottir, Rosa B-
dc.contributor.authorPetrini, John-
dc.contributor.authorWinqvist, Robert-
dc.date.accessioned2008-03-28T09:01:15Z-
dc.date.available2008-03-28T09:01:15Z-
dc.date.issued2006-08-01-
dc.date.submitted2008-03-28-
dc.identifier.citationCarcinogenesis 2006, 27(8):1593-9en
dc.identifier.issn0143-3334-
dc.identifier.pmid16474176-
dc.identifier.doi10.1093/carcin/bgi360-
dc.identifier.urihttp://hdl.handle.net/2336/21772-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractThe Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case-control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P = 0.0004). RAD50 687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5-12.5, P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest that RAD50 687delT is a Finnish founder mutation, not present in the other Nordic cohorts. The RAD50 IVS3-1G>A splicing mutation leading to translational frameshift was observed in one patient, and the NBS1 Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P = 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P = 0.002). These findings suggest an effect for RAD50 and NBS1 haploinsufficiency on genomic integrity and susceptibility to cancer.en
dc.language.isoenen
dc.publisherIrl Press At Oxford University Pressen
dc.relation.urlhttp://carcin.oxfordjournals.org/cgi/content/abstract/27/8/1593en
dc.subject.meshAdulten
dc.subject.meshAgeden
dc.subject.meshBreast Neoplasmsen
dc.subject.meshCase-Control Studiesen
dc.subject.meshCell Cycle Proteinsen
dc.subject.meshCohort Studiesen
dc.subject.meshCytogenetic Analysisen
dc.subject.meshDNA Repair Enzymesen
dc.subject.meshDNA-Binding Proteinsen
dc.subject.meshGene Rearrangementen
dc.subject.meshGenetic Predisposition to Diseaseen
dc.subject.meshGenomic Instabilityen
dc.subject.meshGenotypeen
dc.subject.meshHaplotypesen
dc.subject.meshMass Screeningen
dc.subject.meshMicrosatellite Repeatsen
dc.subject.meshMiddle Ageden
dc.subject.meshMutationen
dc.subject.meshNuclear Proteinsen
dc.subject.meshPedigreeen
dc.subject.meshT-Lymphocytesen
dc.titleRAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability.en
dc.typeArticleen
dc.identifier.journalCarcinogenesisen

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