microRNAs exhibit high frequency genomic alterations in human cancer

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Published online before print June 5, 2006, 10.1073/pnas.0508889103

PNAS | June 13, 2006 | vol. 103 | no. 24 | 9136-9141

OPEN ACCESS ARTICLE

BIOLOGICAL SCIENCES / GENETICS

microRNAs exhibit high frequency genomic alterations in human cancer

Lin Zhang*,,, Jia Huang,, Nuo Yang,¶, Greshock,, Molly S.

Megraw||, Antonis kakis*,**, Shun Liang*, Tara L. Naylor,

Barchetti*, R. Ward, Yao*, Medina,

Ann O'Brien-*, Dionyssios Katsaros, Artemis Hatzigeorgiou||,

Phyllis A. Gimotty, Barbara L. Weber, and Coukos*,,,

*Center for Research on Reproduction and Women's Health, Departments

of Obstetrics and Gynecology and Biostatistics and Epidemiology,

Abramson Family Cancer Research Institute, ¶Cell and Molecular

Biology Graduate Program and Department of Genetics, ||Department of

Genetics and Penn Center for Bioinformatics, University of

Pennsylvania, Philadelphia, PA 19104; Department of Obstetrics and

Gynecology, University of Turin, 10126 Turin, Italy; and **Laboratory

of Gene Expression, Modern Diagnostic and Therapeutic Methods,

Democritus University of Thrace, 69100 androupolis, Greece

Edited by Carlo M. Croce, Ohio State University, Columbus, OH, and

approved April 17, 2006 (received for review October 11, 2005)

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.

genome | noncoding RNA | comparative genomic hybridization