Reduced BRCA1 transcript levels in freshly isolated blood leukocytes from BRCA1 mutation carriers is mutation specific.
Background: BRCA1 mutation carriers face a high lifetime risk of developing both breast and ovarian cancer. Haploinsufficiency is thought to predispose these women to cancer by reducing the pool of available BRCA1 transcript and protein, thereby compromising BRCA1 function. Whether or not cancer-fre...
| Publicado en: | Breast Cancer Research Vol. 18; pp. 1 - 12 |
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| Autores principales: | , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
8/17/2016
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=117593605&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 117593605 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 8/17/2016 vid: 18 pid: 24147 pub: BioMed Central artinfo: ui: 117593605 117593605 NLM27534398 117593605 10.1186/s13058-016-0739-8 NLM27534398 PMC4989508 117593605 ppf: 1 ppct: 11 formats: fmt: @attributes: type: P tig: atl: Reduced BRCA1 transcript levels in freshly isolated blood leukocytes from BRCA1 mutation carriers is mutation specific. aug: au: Chehade, Rania Pettapiece-Phillips, Rachael Salmena, Leonardo Kotlyar, Max Jurisica, Igor Narod, Steven A. Akbari, Mohammad R. Kotsopoulos, Joanne affil: Women's College Research Institute, Women's College Hospital, 76 Grenville Street, 6th Floor, Toronto, ON, Canada sug: subj: Heterozygote Mutation Genes, BRCA Leukocytes Metabolism RNA Adolescence Young Adult Middle Age Cluster Analysis Gene Expression Profiling Genotype Adult Research Subjects Female Adolescent: 13-18 years Middle Aged: 45-64 years Adult: 19-44 years Female ab: Background: BRCA1 mutation carriers face a high lifetime risk of developing both breast and ovarian cancer. Haploinsufficiency is thought to predispose these women to cancer by reducing the pool of available BRCA1 transcript and protein, thereby compromising BRCA1 function. Whether or not cancer-free BRCA1 mutation carriers have lower messenger (m)RNA transcript levels in peripheral blood leukocytes has not been evaluated. The primary aim of this study was to characterize an association between BRCA1 mutation status and BRCA1 mRNA leukocyte expression levels among healthy women with a BRCA1 mutation.Method: RNA was extracted from freshly isolated peripheral blood leukocytes of 58 cancer-free, female participants (22 BRCA1 mutation carriers and 36 non-carriers). The expression levels of 236 cancer-associated genes, including BRCA1, were quantified using the Human Cancer Reference gene panel from the Nanostring Technologies nCounter Analysis System.Results: Multivariate modeling demonstrated that carrying a BRCA1 mutation was the most significant predictor of BRCA1 mRNA levels. BRCA1 mRNA levels were significantly lower in BRCA1 mutation carriers compared to non-carriers (146.7 counts vs. 175.1 counts; P = 0.002). Samples with BRCA1 mutations within exon 11 had lower BRCA1 mRNA levels than samples with mutations within the 5' and 3' regions of the BRCA1 gene (122.1 counts vs. 138.9 and 168.6 counts, respectively; P = 0.003). Unsupervised hierarchical clustering of gene expression profiles from freshly isolated blood leukocytes revealed that BRCA1 mutation carriers cluster more closely with other BRCA1 mutation carriers than with BRCA1 wild-type samples. Moreover, a set of 17 genes (including BRCA1) previously shown to be involved in carcinogenesis, were differentially expressed between BRCA1 mutation carriers and non-carriers.Conclusion: Overall, these findings support the concept of BRCA1 haploinsufficiency wherein a specific mutation results in dosage-dependent alteration of BRCA1 at the transcriptional level. This study is the first to show a decrease in BRCA1 mRNA expression in freshly isolated blood leukocytes from healthy, unaffected BRCA1 mutation carriers. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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