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Background  Using array comparative genomic hybridization (aCGH), a large number of deleted genomic regions have been identified in human cancers. However, subsequent efforts to identify target genes selected for inactivation in these regions have often been challenging.    Methods  We integrated here genome-wide copy number data with gene expression data and non-sense mediated mRNA decay rates in breast cancer cell lines to prioritize gene candidates that are likely to be tumour suppressor genes inactivated by bi-allelic genetic events. The candidates were sequenced to identify potential mutations.    Results  This integrated genomic approach led to the identification of  RIC8A  at 11p15 as a putative candidate target gene for the genomic deletion in the ZR-75-1 breast cancer cell line. We identified a truncating mutation in this cell line, leading to loss of expression and rapid decay of the transcript. We screened 127 breast cancers for  RIC8A  mutations, but did not find any pathogenic mutations. No promoter hypermethylation in these tumours was detected either. However, analysis of gene expression data from breast tumours identified a small group of aggressive tumours that displayed low levels of  RIC8A  transcripts. qRT-PCR analysis of 38 breast tumours showed a strong association between low  RIC8A  expression and the presence of  TP53  mutations (P = 0.006).    Conclusion  We demonstrate a data integration strategy leading to the identification of  RIC8A  as a gene undergoing a classical double-hit genetic inactivation in a breast cancer cell line, as well as  in vivo  evidence of loss of  RIC8A  expression in a subgroup of aggressive  TP53  mutant breast cancers.

Data integration from two microarray platforms identifies bi-allelic genetic inactivation of RIC8Ain a breast cancer cell line