ABSTRACTChromosome translocation and gene fusion arefrequent events in the human genome and are oftenthe cause of many types of tumor. ChimerDB is thedatabase of fusion sequences encompassing bioin-formaticsanalysisofmRNAandexpressedsequencetag (EST) sequences in the GenBank, manual collec-tionofliteraturedataandintegrationwithotherknowndatabase such as OMIM. Our bioinformatics analysisidentifies the fusion transcripts that have non-overlapping alignments at multiple genomic loci.Fusion events at exon–exon borders are selected tofilteroutthecloningartifactsincDNAlibraryprepara-tion.Theresultisclassifiedintotwogroups—genuinechromosome translocation and fusion betweenneighboring genes owing to intergenic splicing. Wealso integrated manually collected literature andOMIM data for chromosome translocation as an aidto assess the validity of each fusion event. The data-base is available at http://genome.ewha.ac.kr/ChimerDB/ for human, mouse and rat genomes.INTRODUCTIONChromosomal aberrations are frequently observed in manyhematologic and solid tumors (1,2). Various large-scale andhigh-throughput techniques, such as chromosome banding(1,3), comparative genomic hybridization (CGH) (4) andﬂuorescence in situ hybridization (FISH) (5), are being usedin modern cancer cytogenetics to detect structural and copynumber changes in chromosomes. The most common type ofmutation among the known cancer genes is chromosomaltranslocation (6). It can deregulate the gene expression bydisrupting the promoter region of the gene or by joining thegene with enhancer elements like immunoglobulin or T-cellreceptorgenes (7). Alternatively, fusion of two coding regionscreates a chimeric gene that encodes a fusion protein thatinterferes with the normal regulating pathways (2,8).The most famous example is the fusion protein BCR–ABL,the target protein of the drug gleevec treating chronic myeloidleukemia(CML)(8,9).CMLisassociatedinmostcaseswithachromosomal translocation between chromosomes 9 and 22that creates the Philadelphia chromosome. The BCR gene inchr22 is fused with the gene ABL in chr9, so called thet(9;22)(q34;q11) translocation. The tyrosine kinase activityof ABL is constantly activated by the BCR gene (GTPaseactivator) in the fusion protein, resulting in the rapid cellularmitosis and inability of the cell to perform apoptosis. Gleevecinhibits the tyrosine kinase ability of the BCR–ABL fusionprotein. Successful development of gleevec opened an era oftargeted molecular therapy.Chimeric sequences can be generated from other mechan-isms too. Two adjacent, independent genes may be co-trans-cribed and the intergenic region is spliced out so that theresulting fused transcript possesses exons from both genes(10). This phenomenon, termed as cotranscription and inter-genic splicing (CoTIS), can lead to fusion protein or alteredpromoter region for the downstream gene in the same way aschromosome translocation. Furthermore, trans-splicing canjoin two independently transcribed mRNA sequences atcanonical exon–exon borders. Even though several cases ofnatural trans-splicing are reported in human (11,12), it is gen-erally considered to be rare and will be ignored in this work.Given the importance of chromosome aberration in cancerdetection,prognosisandtargetidentiﬁcation,itisquitenaturalto search for chimeric sequences in the GenBank. Alterbi andco-workers (13) developed a screening procedure to identifyheterologous, spliced mRNAswith potential origin fromchro-mosomal translocation, mRNA trans-splicing and multi-locustranscription. Hahn et al. (14) extended this approach toinclude expressed sequence tag (EST) sequences that expan-ded the search scope signiﬁcantly. They experimentally veri-ﬁedthepredictedIRA1–RGS17fusioninthebreastcancercellline MCF7. However, they deliberately discarded fusion casesbetween neighboring genes.Curated databases are also available from cancer cytogen-etics community. NCBI’s database of cancer chromosomes(15) integrated the NCI/NCBI SKY/M-FISH and CGH data-base and the NCI Mitelman Database of Chromosome Aber-rations in Cancers. The Cancer Genome Project at the Sanger
['Namshin Kim', 'Pora Kim', 'Seungyoon Nam', 'Seokmin Shin', 'Sanghyuk Lee']
ChimerDB—a knowledgebase for fusion sequences