Finding fusion genes resulting from chromosome rearrangement by analyzing the expressed sequence databases.

Chromosomal rearrangements resulting in gene fusions are frequently involved in carcinogenesis. Here, we describe a semiautomatic procedure for identifying fusion gene transcripts by using publicly available mRNA and EST databases. With this procedure, we have identified 96 transcript sequences that are derived from 60 known fusion genes. Also, 47 or more additional sequences appear to be derived from 20 or more previously unknown putative fusion genes. We have experimentally verified the presence of a previously unknown IRA1/RGS17 fusion in the breast cancer cell line MCF7. The fusion gene encodes the full-length RGS17 protein, a regulator of G protein-coupled signaling, under the control of the IRA1 gene promoter. This study demonstrates that databases of ESTs can be used to discover fusion genes resulting from structural rearrangement of chromosomes.

[1]  C Caldas,et al.  Molecular cytogenetic analysis of breast cancer cell lines , 2000, British Journal of Cancer.

[2]  G. Rubin,et al.  A computer program for aligning a cDNA sequence with a genomic DNA sequence. , 1998, Genome research.

[3]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[4]  T. Shinohara,et al.  Inactivation of Gαz causes disassembly of the Golgi apparatus , 2002, Journal of Cell Science.

[5]  Y. Daaka.  G Proteins in Cancer: The Prostate Cancer Paradigm , 2004, Science's STKE.

[6]  G. Rubin,et al.  Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Allanson,et al.  Familial translocation t(9;16). , 1989, Journal of medical genetics.

[8]  J. Weinstein,et al.  Karyotypic complexity of the NCI-60 drug-screening panel. , 2003, Cancer research.

[9]  Claus Liebmann,et al.  G protein-coupled receptors and their signaling pathways: classical therapeutical targets susceptible to novel therapeutic concepts. , 2004, Current pharmaceutical design.

[10]  M. Santoro,et al.  Cloning and molecular characterization of a novel gene strongly induced by the adenovirus E1A gene in rat thyroid cells , 2003, Oncogene.

[11]  Tom Maniatis,et al.  Promoter Choice Determines Splice Site Selection in Protocadherin α and γ Pre-mRNA Splicing , 2002 .

[12]  H. Sambrook.  Molecular cloning : a laboratory manual. Cold Spring Harbor, NY , 1989 .

[13]  Saverio Alberti,et al.  Detection and analysis of spliced chimeric mRNAs in sequence databanks. , 2003, Nucleic acids research.

[14]  F. Salvatore,et al.  BCR/ABL genes and leukemic phenotype: from molecular mechanisms to clinical correlations , 2002, Oncogene.

[15]  J. Boeynaems,et al.  Cotranscription and Intergenic Splicing of HumanP2Y 11 and SSF1 Genes* , 2001, The Journal of Biological Chemistry.

[16]  N. Nomura,et al.  Complete sequencing and characterization of 21,243 full-length human cDNAs , 2004, Nature Genetics.

[17]  C. Larminie,et al.  Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. , 2004, Brain research. Molecular brain research.

[18]  P. Leder,et al.  Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. , 1982, Science.

[19]  D. Batista,et al.  Molecular analysis of a complex chromosomal rearrangement and a review of familial cases. , 1994, American journal of medical genetics.

[20]  Jun Qin,et al.  Purification and functional characterization of the human N‐CoR complex: the roles of HDAC3, TBL1 and TBLR1 , 2003, The EMBO journal.

[21]  M. Osztovics,et al.  Familial translocation, t(2;5)(p23;q31) , 1975, Clinical genetics.

[22]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[23]  Bernhard Korn,et al.  Toward a Catalog of Human Genes and Proteins: Sequencing and Analysis of 500 Novel Complete Protein Coding Human cDNAs , 2001 .

[24]  Zhi-Jun Duan,et al.  Human Acyl-CoA:Cholesterol Acyltransferase-1 (ACAT-1) Gene Organization and Evidence That the 4.3-Kilobase ACAT-1 mRNA Is Produced from Two Different Chromosomes* , 1999, The Journal of Biological Chemistry.

[25]  B. Johansson,et al.  Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer , 2004, Nature Genetics.

[26]  O. Kallioniemi,et al.  Cloning of BCAS3 (17q23) and BCAS4 (20q13) genes that undergo amplification, overexpression, and fusion in breast cancer † , 2002, Genes, chromosomes & cancer.

[27]  F. Hegardt,et al.  Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Albert,et al.  RGS17/RGSZ2, a Novel Regulator of Gi/o, Gz, and Gq Signaling* , 2004, Journal of Biological Chemistry.