FGFR2 and WDR11 are neighboring oncogene and tumor suppressor gene on human chromosome 10q26.
Oncogenes and tumor suppressor genes are clustered around recombination hot spots or fragile sites in the genome, because double-strand break is the common initial step in translocation, deletion and gene amplification. FGFR2 gene on human chromosome 10q26 is amplified in diffuse-type gastric cancer, while WDR11 gene on human chromosome 10q26 is disrupted in glial tumors. Here, we investigated genomic structure around FGFR2 and WDR11 loci. The FGFR2 gene, consisting of 21 exons, was located within nucleotide position 485637-605687 of NT_030764.5 (reverse orientation), and WDR11 gene was located within nucleotide position 6515786-6574126 of NT_008902.12 (forward orientation). Because nucleotide position 1-91397 of NT_030764.5 corresponded to nucleotide position 6639437-6748623 of NT_008902.12, FGFR2 and WDR11 genes were found to be closely linked in tail-to-tail manner with an interval of ca. 570 kb. Due to the deletion of exon 21 within FGFR2 amplicons, exon 21 is substituted by exon 20 or other aberrant exons in aberrant FGFR2 transcripts previously isolated from KATO-III, OCUM-2M and HSC43 cells. Mapping of aberrant exons and deletion junctions around the WDR11-FGFR2 locus in KATO-III and OCUM-2M cells revealed that inverted-type recombination occurred through end joining of the FGFR2 locus on one allele and that on the other allele. Amplification of FGFR2 gene with such recombination around exon 21 results in exclusion of WDR11 gene from the FGFR2 amplicon. Tumor suppressor genes closely linked to oncogenes might be excluded from amplicon through a breakage-fusion-bridge process during oncogene amplification.
Katoh
Masuko
M
M&M Medical BioInformatics, Narashino 275-0022, Japan. mkatoh@ncc.go.jp
Katoh
Masaru
M
D001932:Brain Neoplasms / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D005091:Exons; D005784:Gene Amplification; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D005910:Glioma / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009857:Oncogenes; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor; C435527:WDR11 protein, human; D000092468:Bromodomain Containing Proteins; C496353:FGFR2 protein, human