title: The complicated copy number alterations in chromosome 7 of a lung cancer cell line is explained by a model based on repeated breakage-fusion-bridge cycles.
abstract: The drug-resistant lung cancer cell line PTX250, which has been previously established by exposure to an anti-cancer drug paclitaxel, has an increased copy number in the MDR1/ABCB1 locus region. In addition, the flanking regions also exhibit aberrant copy numbers, making the copy number profile of chromosome 7 complicated. In this study, we tested whether the breakage-fusion-bridge (BFB) cycle model can explain such copy number alterations. An analysis using fluorescence in situ hybridization (FISH) with a painting probe demonstrated that the aberrant chromosome, designated chromosome 7(amp), was derived from an intact chromosome 7. Using high-density comparative genomic hybridization arrays, we examined the copy number profile in detail and divided chromosome 7(amp) into seven segments. Based on copy numbers of each segment, which were determined using interphase- and metaphase-FISH analysis, we constructed a formation model for the complicated copy number alteration. Six-time BFB cycles and the cycle-termination by healing of broken ends were presupposed in the model. Locations and orientations of the segments observed in chromosome 7(amp) agreed well with those predicted from the model. Telomere addition was also cytogenetically confirmed. In all, it could be concluded that the complicated copy number alteration found in chromosome 7(amp) is generated from the intact chromosome 7 by the repeated BFB cycles.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., 200-Kajiwara, Kamakura, Kanagawa 247-8530, Japan. kitadakno@chugai-pharm.co.jp
authors.forename: Kunio
authors.initials: K
authors.lastname: Kitada
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Yamasaki
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D020223:Chromosome Painting; D002897:Chromosomes, Human, Pair 7; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis