microRNAs exhibit high frequency genomic alterations in human cancer

doi:10.1073/pnas.0508889103

microRNAs exhibit high frequency genomic alterations in human cancer

*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 Alexandroupolis, Greece

Edited by Carlo M. Croce, Ohio State University, Columbus, OH, and approved April 17, 2006
↵ ^‡L.Z., J.H., N.Y., and J.G. contributed equally to this work. (received for review October 11, 2005)

Abstract

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.

Footnotes

^§§To whom correspondence should be addressed. E-mail: gcks{at}mail.med.upenn.edu
Author contributions: L.Z., N.Y., and G.C. designed research; L.Z., J.H., J.G., M.S.M., A.G., S.L., T.L.N., A.B., M.R.W., G.Y., A.M., A.O.-J., and D.K. performed research; J.G., D.K., A.H., P.A.G., and B.L.W. contributed new reagents/analytic tools; L.Z., J.H., J.G., M.S.M., A.H., P.A.G., B.L.W., and G.C. analyzed data; and L.Z., N.Y., and G.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

aCGH,

array comparative genomic hybridization;

miRNA,

microRNA.
Freely available online through the PNAS open access option.