%0 Journal Article %J Proc Natl Acad Sci U S A %D 2008 %T Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. %A Zhang, Lin %A Volinia, Stefano %A Bonome, Tomas %A Calin, George Adrian %A Greshock, Joel %A Yang, Nuo %A Liu, Chang-Gong %A Giannakakis, Antonis %A Alexiou, Pangiotis %A Hasegawa, Kosei %A Johnstone, Cameron N %A Megraw, Molly S %A Adams, Sarah %A Lassus, Heini %A Huang, Jia %A Kaur, Sippy %A Liang, Shun %A Sethupathy, Praveen %A Leminen, Arto %A Simossis, Victor A %A Sandaltzopoulos, Raphael %A Naomoto, Yoshio %A Katsaros, Dionyssios %A Gimotty, Phyllis A %A DeMichele, Angela %A Huang, Qihong %A Bützow, Ralf %A Rustgi, Anil K %A Weber, Barbara L %A Birrer, Michael J %A Hatzigeorgiou, Artemis G %A Croce, Carlo M %A Coukos, George %K DNA, Neoplasm %K Down-Regulation %K Epigenesis, Genetic %K Epithelial Cells %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Genome, Human %K Humans %K MicroRNAs %K Neoplasm Staging %K Ovarian Neoplasms %K Ribonuclease III %K RNA, Messenger %K Survival Analysis %X

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that function as negative gene regulators. miRNA deregulation is involved in the initiation and progression of human cancer; however, the underlying mechanism and its contributions to genome-wide transcriptional changes in cancer are still largely unknown. We studied miRNA deregulation in human epithelial ovarian cancer by integrative genomic approach, including miRNA microarray (n = 106), array-based comparative genomic hybridization (n = 109), cDNA microarray (n = 76), and tissue array (n = 504). miRNA expression is markedly down-regulated in malignant transformation and tumor progression. Genomic copy number loss and epigenetic silencing, respectively, may account for the down-regulation of approximately 15% and at least approximately 36% of miRNAs in advanced ovarian tumors and miRNA down-regulation contributes to a genome-wide transcriptional deregulation. Last, eight miRNAs located in the chromosome 14 miRNA cluster (Dlk1-Gtl2 domain) were identified as potential tumor suppressor genes. Therefore, our results suggest that miRNAs may offer new biomarkers and therapeutic targets in epithelial ovarian cancer.

%B Proc Natl Acad Sci U S A %V 105 %P 7004-9 %8 2008 May 13 %G eng %N 19 %R 10.1073/pnas.0801615105 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2006 %T microRNAs exhibit high frequency genomic alterations in human cancer. %A Zhang, Lin %A Huang, Jia %A Yang, Nuo %A Greshock, Joel %A Megraw, Molly S %A Giannakakis, Antonis %A Liang, Shun %A Naylor, Tara L %A Barchetti, Andrea %A Ward, Michelle R %A Yao, George %A Medina, Angelica %A O'brien-Jenkins, Ann %A Katsaros, Dionyssios %A Hatzigeorgiou, Artemis %A Gimotty, Phyllis A %A Weber, Barbara L %A Coukos, George %K Breast Neoplasms %K Female %K Gene Dosage %K Gene Expression Profiling %K Humans %K MicroRNAs %K Neoplasms %K Nucleic Acid Hybridization %K Oligonucleotide Array Sequence Analysis %K Ovarian Neoplasms %K Statistics as Topic %X

MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution array-based comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1%), breast cancer (72.8%), and melanoma (85.9%), where copy number alterations observed in >15% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of Dicer1, Argonaute2, and other miRNA-associated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.

%B Proc Natl Acad Sci U S A %V 103 %P 9136-41 %8 2006 Jun 13 %G eng %N 24 %R 10.1073/pnas.0508889103