Abstract Identification of cancer biomarkers depends on measuring the differential genotypes and phenotypes between normal and disease tissues. However, cancer is characterized by accumulation of genetic lesions and heterogeneity, and hence great efforts need to be invested to distinguish driver versus passenger abnormalities. Several strategies have been employed to achieve the distinction, including conservation of genetic lesions between mouse models and human diseases, gain of copy number/amplification, deletion/loss of heterogeneity, and epigenetic alterations. Redundancy of some microRNA (miRNA) genes has been an interesting finding and its biological significance is not clear. These redundant miRNA loci have different genomic locations and are transcribed independently, and yet are processed into identical mature miRNA, and these loci are annotated as -1, -2, -3, etc, following the miRNA gene name. Selective expression of these loci could be a regulatory strategy to control expression of other genomically associated genetic elements that are critical to the disease processes, while the required level of mature miRNA can still be maintained by leveraging the redundancy. The proof-of-principle of this rationale was to compare between normal breast and breast cancer cell lines the expression of miRNA genes that have multiple loci and are associated with other genetic elements such as other miRNA genes within the same clusters or their host protein-coding/non-coding genes. This investigation narrowed down to mir-100 gene that is clustered with let-7a-2 gene, both of which lost expression completely in three luminal-type breast cancer cell lines but not in one basal-type cell line and normal breast, whereas expression from let-7a-1 and let-7a-3 remains unchanged between normal breast and cell lines tested. Loss of mir-100 and let-7a-2 expression appears to be caused at least by loss of one copy or both copies of these two loci. Deletion of mir-100 locus can also be detected in clinical specimens. These results suggest that this method might effectively distinguish driver versus passenger differentially expressed genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1159. doi:10.1158/1538-7445.AM2011-1159