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Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas.

Martínez-A C, van Wely KH - Carcinogenesis (2011)

Bottom Line: This means that changes involving intact chromosomes accompany breakage-induced alterations.Here, we discuss how the experimental systems translate to human carcinomas and compare the theoretical breakage products to data from patient material and cancer cell lines.Centromere fission, not telomere erosion, is therefore the most probably trigger of CIN and early carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, UAM Campus Cantoblanco, 28049 Madrid, Spain.

ABSTRACT
The majority of sporadic carcinomas suffer from a kind of genetic instability in which chromosome number changes occur together with segmental defects. This means that changes involving intact chromosomes accompany breakage-induced alterations. Whereas the causes of aneuploidy are described in detail, the origins of chromosome breakage in sporadic carcinomas remain disputed. The three main pathways of chromosomal instability (CIN) proposed until now (random breakage, telomere fusion and centromere fission) are largely based on animal models and in vitro experiments, and recent studies revealed several discrepancies between animal models and human cancer. Here, we discuss how the experimental systems translate to human carcinomas and compare the theoretical breakage products to data from patient material and cancer cell lines. The majority of chromosomal defects in human carcinomas comprises pericentromeric breaks that are captured by healthy telomeres, and only a minor proportion of chromosome fusions can be attributed to telomere erosion or random breakage. Centromere fission, not telomere erosion, is therefore the most probably trigger of CIN and early carcinogenesis. Similar centromere-telomere fusions might drive a subset of congenital defects and evolutionary chromosome changes.

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Related in: MedlinePlus

Classification of segmental defects in tumor samples. Spectral karyotyping analyses corresponding to 98 human carcinomas from the NCBI SKY/CGH database (93) were inspected for structural alterations. Samples without apparent structural alterations (seven cases) or bearing >25 alterations (four cases) were discarded. Alterations were classified according to breakpoint and fusion products. Multiple copies of the same alteration in a single sample were counted as a single event, as they correspond to aneuploid state of entire fusion products and do not involve de novo breakage. The majority of products involve centromeric fission, and only a minor proportion can be attributed to telomere–telomere fusion.
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fig5: Classification of segmental defects in tumor samples. Spectral karyotyping analyses corresponding to 98 human carcinomas from the NCBI SKY/CGH database (93) were inspected for structural alterations. Samples without apparent structural alterations (seven cases) or bearing >25 alterations (four cases) were discarded. Alterations were classified according to breakpoint and fusion products. Multiple copies of the same alteration in a single sample were counted as a single event, as they correspond to aneuploid state of entire fusion products and do not involve de novo breakage. The majority of products involve centromeric fission, and only a minor proportion can be attributed to telomere–telomere fusion.

Mentions: The analysis of copy number changes alone does not depict the topology of breakage and fusion. Microscopy based techniques, for example spectral karyotyping and fluorescent in situ hybridization, yield a much more visual image of chromosome fragments and their instability. Optical techniques showed that chromosome arms are normally not found alone but rapidly fuse to other fragments or intact chromosomes (83,91). Some of the copy number changes observed in the large-scale analyses are therefore brought about by chromosome arms that ‘hitch a ride’ on the ends of healthy chromosomes (Figure 4). When viewed by microscopy, fused chromosomes appear to grow from a telomere; this observation might have contributed to the focus on telomere defects. Close inspection of the formed products, however, shows that the fusion point comprises a centromere and a telomere, and analysis by banding techniques shows that a fragment the size of a whole arm attaches to the end of a healthy chromosome in a tandem orientation (91). A classification of products described in literature (94) and spectral karyotyping databases (93) indicate that tandem fusions are much more common than antiparallel fusions (Figure 5). Also the other products of centromere fission—for example centromeric fusion of two arms and isochromosomes (84,95)—are common in tumor samples.


Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas.

Martínez-A C, van Wely KH - Carcinogenesis (2011)

Classification of segmental defects in tumor samples. Spectral karyotyping analyses corresponding to 98 human carcinomas from the NCBI SKY/CGH database (93) were inspected for structural alterations. Samples without apparent structural alterations (seven cases) or bearing >25 alterations (four cases) were discarded. Alterations were classified according to breakpoint and fusion products. Multiple copies of the same alteration in a single sample were counted as a single event, as they correspond to aneuploid state of entire fusion products and do not involve de novo breakage. The majority of products involve centromeric fission, and only a minor proportion can be attributed to telomere–telomere fusion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3106440&req=5

fig5: Classification of segmental defects in tumor samples. Spectral karyotyping analyses corresponding to 98 human carcinomas from the NCBI SKY/CGH database (93) were inspected for structural alterations. Samples without apparent structural alterations (seven cases) or bearing >25 alterations (four cases) were discarded. Alterations were classified according to breakpoint and fusion products. Multiple copies of the same alteration in a single sample were counted as a single event, as they correspond to aneuploid state of entire fusion products and do not involve de novo breakage. The majority of products involve centromeric fission, and only a minor proportion can be attributed to telomere–telomere fusion.
Mentions: The analysis of copy number changes alone does not depict the topology of breakage and fusion. Microscopy based techniques, for example spectral karyotyping and fluorescent in situ hybridization, yield a much more visual image of chromosome fragments and their instability. Optical techniques showed that chromosome arms are normally not found alone but rapidly fuse to other fragments or intact chromosomes (83,91). Some of the copy number changes observed in the large-scale analyses are therefore brought about by chromosome arms that ‘hitch a ride’ on the ends of healthy chromosomes (Figure 4). When viewed by microscopy, fused chromosomes appear to grow from a telomere; this observation might have contributed to the focus on telomere defects. Close inspection of the formed products, however, shows that the fusion point comprises a centromere and a telomere, and analysis by banding techniques shows that a fragment the size of a whole arm attaches to the end of a healthy chromosome in a tandem orientation (91). A classification of products described in literature (94) and spectral karyotyping databases (93) indicate that tandem fusions are much more common than antiparallel fusions (Figure 5). Also the other products of centromere fission—for example centromeric fusion of two arms and isochromosomes (84,95)—are common in tumor samples.

Bottom Line: This means that changes involving intact chromosomes accompany breakage-induced alterations.Here, we discuss how the experimental systems translate to human carcinomas and compare the theoretical breakage products to data from patient material and cancer cell lines.Centromere fission, not telomere erosion, is therefore the most probably trigger of CIN and early carcinogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, UAM Campus Cantoblanco, 28049 Madrid, Spain.

ABSTRACT
The majority of sporadic carcinomas suffer from a kind of genetic instability in which chromosome number changes occur together with segmental defects. This means that changes involving intact chromosomes accompany breakage-induced alterations. Whereas the causes of aneuploidy are described in detail, the origins of chromosome breakage in sporadic carcinomas remain disputed. The three main pathways of chromosomal instability (CIN) proposed until now (random breakage, telomere fusion and centromere fission) are largely based on animal models and in vitro experiments, and recent studies revealed several discrepancies between animal models and human cancer. Here, we discuss how the experimental systems translate to human carcinomas and compare the theoretical breakage products to data from patient material and cancer cell lines. The majority of chromosomal defects in human carcinomas comprises pericentromeric breaks that are captured by healthy telomeres, and only a minor proportion of chromosome fusions can be attributed to telomere erosion or random breakage. Centromere fission, not telomere erosion, is therefore the most probably trigger of CIN and early carcinogenesis. Similar centromere-telomere fusions might drive a subset of congenital defects and evolutionary chromosome changes.

Show MeSH
Related in: MedlinePlus