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Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.

ABSTRACT: Overexpression of the Aurora A kinase has been shown to have prognostic value in breast cancer. Previously, we showed a significant association between AURKA gene amplification and BRCA2 mutation in breast cancer. The aim of this study was to assess the prognostic impact of Aurora A overexpression on breast cancer arising in BRCA2 mutation carriers. Aurora A expression was evaluated by immunohistochemistry on breast tumour tissue microarrays from 107 BRCA2 999del5 mutation carriers and 284 of sporadic origin. Prognostic value of Aurora A nuclear staining was estimated in relation to clinical markers and adjuvant treatment, using multivariate Cox's proportional hazards ratio regression model. BRCA2 wild-type allele loss was measured by TaqMan in BRCA2 mutated tumour samples. All statistical tests were two sided. Multivariate analysis of breast cancer-specific survival, including proliferative markers and treatment, indicated independent prognostic value of Aurora A nuclear staining for BRCA2 mutation carriers (hazards ratio?=?7.06; 95% confidence interval?=?1.23-40.6; p?=?0.028). Poor breast cancer-specific survival of BRCA2 mutation carriers was found to be significantly associated with combined Aurora A nuclear expression and BRCA2 wild type allele loss in tumours (p?

SUBMITTER: Aradottir M

PROVIDER: S-EPMC4858119 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.

Aradottir Margret M Reynisdottir Sigridur T ST Stefansson Olafur A OA Jonasson Jon G JG Sverrisdottir Asgerdur A Tryggvadottir Laufey L Eyfjord Jorunn E JE Bodvarsdottir Sigridur K SK

The journal of pathology. Clinical research 20141107 1

Overexpression of the Aurora A kinase has been shown to have prognostic value in breast cancer. Previously, we showed a significant association between AURKA gene amplification and BRCA2 mutation in breast cancer. The aim of this study was to assess the prognostic impact of Aurora A overexpression on breast cancer arising in BRCA2 mutation carriers. Aurora A expression was evaluated by immunohistochemistry on breast tumour tissue microarrays from 107 BRCA2 999del5 mutation carriers and 284 of sp ...[more]

PMID: 27499891

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Project description:INTRODUCTION:Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. METHODS:We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. RESULTS:We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBP?, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). CONCLUSIONS:Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.

Project description:Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in-silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analysed in-vitro and in-vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, DBP and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2, which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele. Total gene expression of normal breast sample from healthy controls. This submission represents transcriptome component of study.

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Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.

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Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers.

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