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Research Article

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

George Adrian Calin, Cinzia Sevignani, Calin Dan Dumitru, Terry Hyslop, Evan Noch, Sai Yendamuri, Masayoshi Shimizu, Sashi Rattan, Florencia Bullrich, Massimo Negrini, and Carlo M. Croce
  1. Departments of *Microbiology and Immunology and ‡Medicine, Division of Clinical Pharmacology, Biostatistics Section, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; and §Dipartimento di Medicina Sperimentale e Diagnostica e Centro Interdipartimentale per la Ricerca sul Cancro, Università di Ferrara, Ferrara 44100, Italy

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PNAS March 2, 2004 101 (9) 2999-3004; https://doi.org/10.1073/pnas.0307323101
George Adrian Calin
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Cinzia Sevignani
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Calin Dan Dumitru
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Terry Hyslop
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Evan Noch
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Sai Yendamuri
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Masayoshi Shimizu
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Sashi Rattan
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Florencia Bullrich
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Massimo Negrini
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Carlo M. Croce
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  1. Contributed by Carlo M. Croce, December 29, 2003

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Abstract

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

Footnotes

  • ↵ ¶ To whom correspondence should be addressed at: Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107. E-mail: carlo.croce{at}mail.tju.edu.

  • ↵ † G.A.C. and C.S. contributed equally to this work.

  • Abbreviations: miR, microRNA; B-CLL, B cell chronic lymphocytic leukemias; LOH, loss of heterozygosity; CAGR, cancer-associated genomic region; IRR, incidence rate ratio; TS, tumor suppressor; FRA, fragile site; HPV, human papilloma virus; OG, oncogene; HD, homozygous deletion; HOX, homeobox.

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Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers
George Adrian Calin, Cinzia Sevignani, Calin Dan Dumitru, Terry Hyslop, Evan Noch, Sai Yendamuri, Masayoshi Shimizu, Sashi Rattan, Florencia Bullrich, Massimo Negrini, Carlo M. Croce
Proceedings of the National Academy of Sciences Mar 2004, 101 (9) 2999-3004; DOI: 10.1073/pnas.0307323101

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Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers
George Adrian Calin, Cinzia Sevignani, Calin Dan Dumitru, Terry Hyslop, Evan Noch, Sai Yendamuri, Masayoshi Shimizu, Sashi Rattan, Florencia Bullrich, Massimo Negrini, Carlo M. Croce
Proceedings of the National Academy of Sciences Mar 2004, 101 (9) 2999-3004; DOI: 10.1073/pnas.0307323101
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