Transcriptomics,Genomics

Dataset Information

25

BRCA1 Haploinsufficiency Leads to Altered Expression of Genes Involved in Cellular Proliferation and Development


ABSTRACT: Background: The BRCA1 protein has been shown to play critical roles in several molecular pathways, but the specific defect(s) that promote breast and ovarian carcinogenesis remain a mystery. Furthermore, while mutations that result in a truncated protein can unequivocally be called disease-causing, many other variants mutations have poorly defined clinical significance. Given these factors, development of a functional assay for BRCA1 is a significant clinical priority, but presents significant biological challenges. Methodology and Significant Findings: We have developed a novel function-based assay for BRCA1 carrier identification by examining the effect of loss of a single copy of BRCA1 on global gene expression levels. Comparison of the gene expression profiles of undamaged, actively cycling EBV-transformed lymphocytes allowed accurate discrimination between BRCA1+/+ and BRCA1+/- cells. The best predictor was 100% (16/16) accurate in predicting BRCA1 status in an independent test set; the overall sensitivity and specificity of the test are 84% and 92%, respectively, when the training set data (53 samples) is also included. A set of 22 genes was identified by two distinct analytical approaches, including a set of 11 genes (TBX21, MX2, IFIT1, IFIT2, IFIT3, GLDC, F13A1, SOX4, LCK, HERC5, USP18) that could be linked in a single pathway encompassing cellular proliferation and development. By contrast, analysis of the same samples for global gene expression level changes following irradiation did not support the development of an accurate class predictor. Conclusions and Significance: Our results support the idea that the fundamental defect resulting from BRCA1 mutation is a reduction in cellular differentiation, and that changes in the DNA damage response require inactivation of the second BRCA1 allele. Given that the class predictor we have developed was based on unperturbed cells, this work could ultimately lead to the development of a rapid and accurate test for identification of BRCA1 mutation carriers. Overall design: 69 cell lines consist of 38 control (BRCA1+/+) and 31 BRCA1 mutation carriers (BRCA1+/-), two color arrays, non radiated vs. radiated for each cell line. Although the experiment was done to allow for analysis of radiation-dependent effects (Cy5/Cy3 ratio), the results reported in Sample Data Tables are from unperturbed cells (Cy3 one color data only).

INSTRUMENT(S): Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)

SUBMITTER: Scott Davey  

PROVIDER: GSE19541 | GEO | 2014-12-12

SECONDARY ACCESSION(S): PRJNA122319

REPOSITORIES: GEO

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Publications

BRCA1 haploinsufficiency leads to altered expression of genes involved in cellular proliferation and development.

Feilotter Harriet E HE   Michel Claire C   Uy Paolo P   Bathurst Lauren L   Davey Scott S  

PloS one 20140620 6


The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1.  ...[more]

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