Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas - PubMed (original) (raw)
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Centromere fission, not telomere erosion, triggers chromosomal instability in human carcinomas
Carlos Martínez-A et al. Carcinogenesis. 2011 Jun.
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.
Figures
Fig. 1.
Copy number alterations involve chromosome breaks. As aneuploidy strictly refers to numerical changes of whole chromosomes, segmental gains and losses require that part of a chromosome has obtained a different copy number from the remainder of the same chromosome. The example shows chromosome 11 from Figure 3. Segmental gains and losses create a growth advantage by uncoupling the copy number of oncogenes (e.g. cycD1) and tumor suppressor genes (e.g. chk1) from general gene dosage. Frequently, the gains and losses over a single chromosome are complementary, as segments without gains are not copy number neutral but normally show losses. Intrachromosomal segment borders that delineate copy number alterations correspond to unprotected (reactive) ends that are functionally equivalent to breaks.
Fig. 2.
Comparison of chromosome breakage pathways Three models, random breakage (left), telomere fusion (middle), and centromere fission (right) are represented. For each model, initial defects are shown on the upper row, primary fusions on the second row and later products on the third row. Random breaks are depicted with purple arrows and site specificity is indicated with yellow arrows. Whereas random breaks are the main products in the random breakage and telomere fusion models, arm-level breaks are generated first in the centromere fission model and random breaks form only after secondary fusion has taken place. Fusions in the telomere erosion model are telomere to telomere (blue) and thus antiparallel, whereas fusions in the centromere fission model are centromere (red) to telomere and thus tandem (black arrows, oriented from the centromere to the telomere).
Fig. 3.
Chromosome breaks frequently liberate whole arms Copy number analysis of 844 liver carcinomas (A) and 1827 head and neck squamous cell carcinomas (B) were retrieved from the Progenetix database (90). For each type of carcinoma, gains are indicated in green (right) and losses in red (left). Blue lines indicate centromere positions. Chromosomes that bear evidence of centromere fission are indicated with an arrow. Analysis of 3131 profiles showed a similar preference for whole arm gains and losses in a wide range of carcinomas (43). The biphasic pattern of chromosome 11q probably is a result of whole arm amplification followed by loss of the distal segment.
Fig. 4.
Broken arms fuse to the end of chromosomes. Example of a molecular cytogenetic analysis of a neuroectodermal tumor (92). The skygram was retrieved from the NCBI SKY/CGH database (93). The main structural alterations observed correspond to centromeric breaks (chromosomes 13 and 21) followed by fusion to telomeres (chromosomes 8, 15 and 20). Arrows indicate tandem orientation of the fusions. The fusion of chromosome 21 to chromosomes 8 and 15 classifies as a jumping translocation.
Fig. 5.
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.
Fig. 6.
Early events leading to CIN. An uncorrected merotelic attachment causes chromosome breakage at the centromeric region (yellow arrow), resulting in two reactive chromosome arms. The arm without a centromere is easily lost in subsequent cell divisions or can be rescued by a translocation. The centromere-containing arm can replicate and segregate. The centromere-containing arm thus forms a reactive species that persists during subsequent cell divisions. The arm bearing the first break can self-ligate, forming a pseudodicentric chromosome, or fuse to a healthy chromosome (dark green), forming a dicentric chromosome bearing an interstitial telomere. Capture of a dicentric chromosome by two spindle poles leads to secondary breaks (purple arrows), propagating BFB cycles. Dashed lines indicate events that stabilize chromosome arms with breaks. Figure adapted from (12).
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