Carcinogenesis Advance Access originally published online on March 19, 2008
Carcinogenesis 2008 29(9):1710-1716; doi:10.1093/carcin/bgn073
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Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs



1 Department of Medicine, McGill University, Montréal, Québec H3G 1A4, Canada
2 Health Sector, Biotechnology Research Institute, National Research Council of Canada, 6100 Royalmount Avenue, Montréal, Québec H4P 2R2, Canada
* To whom correspondence should be addressed. Tel: +1 514 496 6318; Fax: +1 514 496 6319; Email: shi.shen{at}cnrc-nrc.gc.ca
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level to lead to mRNA degradation or repressed protein production. The expression of miRNA is deregulated in many types of cancers. To determine whether genetic alterations in miRNA genes are associated with cancers, we have systematically screened sequence variations in several hundred human miRNAs from >100 human tumor tissues and 20 cancer cell lines. We identified 8 new single-nucleotide polymorphisms (SNPs) and 14 novel mutations (or very rare SNPs) that specifically present in human cancers. These mutations/SNPs are distributed in the regions of pri-, pre- and even mature miRNAs, respectively. Importantly, whereas most of the mutations did not exert detectable effects on miRNA function, a G
A mutation at 19 nt downstream of miRNA let-7e led to a significant reduction of its expression in vivo, indicating that miRNA mutation could contribute to tumorigenesis. These data suggest that further screening for genetic variations in miRNA genes from a wide variety of human cancers should increase the discovery and identification of molecular diagnostic and therapeutic targets and complement the mutation analysis of consensus coding sequences in human cancers.
Abbreviations: miRNA, microRNA; PCR, polymerase chain reaction; RT, reverse transcription; SNP, single-nucleotide polymorphism; ssRNA, single-stranded RNA
These authors contributed equally to this work. Received December 21, 2007; revised February 19, 2008; accepted March 7, 2008.
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