Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity

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Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. / Gisselsson Nord, David; Pettersson, Louise; Höglund, Mattias; Heidenblad, Markus; Gorunova, Ludmila; Wiegant, J; Mertens, Fredrik; Dal Cin, P; Mitelman, Felix; Mandahl, Nils.

In: Proceedings of the National Academy of Sciences, Vol. 97, No. 10, 2000, p. 5357-5362.

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TY - JOUR

T1 - Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity

AU - Gisselsson Nord, David

AU - Pettersson, Louise

AU - Höglund, Mattias

AU - Heidenblad, Markus

AU - Gorunova, Ludmila

AU - Wiegant, J

AU - Mertens, Fredrik

AU - Dal Cin, P

AU - Mitelman, Felix

AU - Mandahl, Nils

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.090013497

DO - 10.1073/pnas.090013497

M3 - Article

VL - 97

SP - 5357

EP - 5362

JO - Proceedings of the National Academy of Sciences

T2 - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 10

ER -