A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer

Hdl Handle:
http://hdl.handle.net/10147/323241
Title:
A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer
Authors:
Dorairaj, Jemima J; Salzman, David W; Wall, Deirdre; Rounds, Tiffany; Preskill, Carina; Sullivan, Catherine AW; Lindner, Robert; Curran, Catherine; Lezon-Geyda, Kim; McVeigh, Terri; Harris, Lyndsay; Newell, John; Kerin, Michael J; Wood, Marie; Miller, Nicola; Weidhaas, Joanne B
Citation:
Dorairaj JJ et al. A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer. BMC Cancer. 2014 Jun 10;14(1):421
Issue Date:
10-Jun-2014
URI:
http://dx.doi.org/10.1186/1471-2407-14-421; http://hdl.handle.net/10147/323241
Abstract:
Abstract Background A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer. Methods The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. Results Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort. Conclusion A variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.
Item Type:
Article
Language:
en
Keywords:
BREAST CANCER; GENETICS

Full metadata record

DC FieldValue Language
dc.contributor.authorDorairaj, Jemima Jen_GB
dc.contributor.authorSalzman, David Wen_GB
dc.contributor.authorWall, Deirdreen_GB
dc.contributor.authorRounds, Tiffanyen_GB
dc.contributor.authorPreskill, Carinaen_GB
dc.contributor.authorSullivan, Catherine AWen_GB
dc.contributor.authorLindner, Roberten_GB
dc.contributor.authorCurran, Catherineen_GB
dc.contributor.authorLezon-Geyda, Kimen_GB
dc.contributor.authorMcVeigh, Terrien_GB
dc.contributor.authorHarris, Lyndsayen_GB
dc.contributor.authorNewell, Johnen_GB
dc.contributor.authorKerin, Michael Jen_GB
dc.contributor.authorWood, Marieen_GB
dc.contributor.authorMiller, Nicolaen_GB
dc.contributor.authorWeidhaas, Joanne Ben_GB
dc.date.accessioned2014-07-17T08:35:08Z-
dc.date.available2014-07-17T08:35:08Z-
dc.date.issued2014-06-10-
dc.identifier.citationDorairaj JJ et al. A germline mutation in the BRCA1 3'UTR predicts Stage IV breast cancer. BMC Cancer. 2014 Jun 10;14(1):421en_GB
dc.identifier.urihttp://dx.doi.org/10.1186/1471-2407-14-421-
dc.identifier.urihttp://hdl.handle.net/10147/323241-
dc.description.abstractAbstract Background A germline, variant in the BRCA1 3’UTR (rs8176318) was previously shown to predict breast and ovarian cancer risk in women from high-risk families, as well as increased risk of triple negative breast cancer. Here, we tested the hypothesis that this variant predicts tumor biology, like other 3’UTR mutations in cancer. Methods The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression, and altered response to external stimuli was tested in vitro using a luciferase reporter assay. Gene expression was further tested in vivo by immunoflourescence staining on breast tumor tissue, comparing triple negative patient samples with the variant (TG or TT) or non-variant (GG) BRCA1 3’UTR. To determine the significance of the variant on clinically relevant endpoints, a comprehensive collection of West-Irish breast cancer patients were tested for the variant. Finally, an association of the variant with breast screening clinical phenotypes was evaluated using a cohort of women from the High Risk Breast Program at the University of Vermont. Results Luciferase reporters with the BRCA1-3’UTR-variant (T allele) displayed significantly lower gene expression, as well as altered response to external hormonal stimuli, compared to the non-variant 3’UTR (G allele) in breast cancer cell lines. This was confirmed clinically by the finding of reduced BRCA1 gene expression in triple negative samples from patients carrying the homozygous TT variant, compared to non-variant patients. The BRCA1-3’UTR-variant (TG or TT) also associated with a modest increased risk for developing breast cancer in the West-Irish cohort (OR = 1.4, 95% CI 1.1-1.8, p = 0.033). More importantly, patients with the BRCA1-3’UTR-variant had a 4-fold increased risk of presenting with Stage IV disease (p = 0.018, OR = 3.37, 95% CI 1.3-11.0). Supporting that this finding is due to tumor biology, and not difficulty screening, obese women with the BRCA1-3’UTR-variant had significantly less dense breasts (p = 0.0398) in the Vermont cohort. Conclusion A variant in the 3’UTR of BRCA1 is functional, leading to decreased BRCA1 expression, modest increased breast cancer risk, and most importantly, presentation with stage IV breast cancer, likely due to aggressive tumor biology.-
dc.language.isoenen
dc.subjectBREAST CANCERen_GB
dc.subjectGENETICSen_GB
dc.titleA germline mutation in the BRCA1 3'UTR predicts Stage IV breast canceren_GB
dc.typeArticleen
dc.language.rfc3066en-
dc.rights.holderJemima J Dorairaj et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2014-06-17T07:03:18Z-
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