Chromosomal Breakage-Fusion-Bridge Events Cause Genetic Intratumor Heterogeneity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 10; pp. 5357 - 5362
• Main Authors: Gisselsson, David, Pettersson, Louise, Hoglund, Mattias, Heidenblad, Markus, Gorunova, Ludmila, Wiegant, Joop, Mertens, Fredrik, Cin, Paola Dal, Mitelman, Felix, Mandahl, Nils
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 09.05.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Anaphase; Basic Medicine; Biological Sciences; Cell lines; Chromosome Aberrations; Chromosome Banding; Chromosomes; Chromosomes, Human - genetics; Chromosomes, Human - radiation effects; Crosses, Genetic; Genetic heterogeneity; Genetics; Humans; In Situ Hybridization, Fluorescence; Irradiation; Karyotyping; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Models, Genetic; Neoplasms - genetics; Neoplasms - pathology; Neoplasms - surgery; Reverse Transcriptase Polymerase Chain Reaction; Ring chromosomes; Transcription, Genetic; Tumor cell line; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.090013497

It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cycles may cause variability of phenotypic and genetic traits within a cell population. Because intercellular heterogeneity is often found in neoplastic tissues, we investigated the occurrence of BFB events in human solid tumors. Evidence of frequent BFB events was found in malignancies that showed unspecific chromosome aberrations, including ring chromosomes, dicentric chromosomes, and telomeric associations, as well as extensive intratumor heterogeneity in the pattern of structural changes but not in tumors with tumor-specific aberrations and low variability. Fluorescence in situ hybridization analysis demonstrated that chromosomes participating in anaphase bridge formation were involved in a significantly higher number of structural aberrations than other chromosomes. Tumors with BFB events showed a decreased elimination rate of unstable chromosome aberrations after irradiation compared with normal cells and other tumor cells. This result suggests that a combination of mitotically unstable chromosomes and an elevated tolerance to chromosomal damage leads to constant genomic reorganization in many malignancies, thereby providing a flexible genetic system for clonal evolution and progression.