High Frequency Genome Copy Number Abnormalities Of Micrornas In Human Cancer.

6111 MicroRNAs (miRNAs) are endogenous ∼22nt non-coding RNAs, which regulate gene expression in a sequence-specific manner via mRNA degradation or translational repression. To genome-wide determine the DNA copy number abnormalities of miRNA genes, high-resolution array-based comparative genomic hybridization (aCGH) was used in this study. Genomic location of 207 known human miRNA genes was identified in the miRNA registry. A total of 101 ovarian cancer specimens (86 primary tumor and 15 cell lines), 73 breast cancer specimens (55 primary tumors and 18 cell lines) as well as 46 melanoma cell lines were initially examined. We found that the DNA copy number of 17.9% (37/207), 53.6% (111/207) and 40.1% (83/207) miRNA genes was significantly (in >20% samples) altered in ovarian cancer, breast cancer and melanoma, respectively. In breast cancer, the ratio of copy number with gains to losses was 4.1, in contrast to 1.6 in ovarian cancer and 1.37 in melanoma. Genome copy number abnormalities of miRNAs were distributed on all chromosomes except chromosome 18 and 21. Ovarian and breast cancer shared 12 and 6 miRNA genes with copy number gains and losses respectively. Furthermore, 5 miRNA genes with copy number gains and 6 with losses were shared by all three types of cancer. Finally, 63 miRNA genes had no copy number change in any of those cancer samples. miRNA genes are frequently clustered in the human genome with an arrangement and expression pattern implying transcription as a poly-cistronic primary transcript. In 207 miRNA genes analyzed here, 102 are located in 37 clusters. We found that clustered miRNA genes could simultaneously lose or gain copy number in human cancer. miRNA genes are also frequently located in the introns of protein-coding genes, suggesting likely simultaneous copy number changes with the corresponding protein-coding genes in human cancer. In 207 analyzed miRNA genes, 51 are located in intron. Among them, 8, 24 and 18 had altered copy number in ovarian cancer, breast cancer and melanoma, respectively. In summary, we reported genome-wide, high-frequency miRNA copy number alterations in cancer. In contemplation of previous report that miRNAs are frequently located in cancer-associated regions or in fragile sites, we think that genetic alterations of miRNAs may constitute a critical step in cancer development, e.g., in the expressional control of genes involved in cancer, in particular, tumor suppressor genes and oncogenes. We thus propose that genetic alterations of miRNAs may initiate and/or accelerate the imbalance of gene expression in cancer, accelerating oncogenesis and promoting tumor growth. Rescued expression of down-regulated or functionally deficient miRNAs and/or inhibition of over-expressed/functioning miRNAs should contribute to the rebalanced expression of large gene clusters and impede tumor growth, and therefore, provide a novel therapeutic stratagem for human cancer.