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

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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Mechanisms of chromosomal instability and carcinogenesis

Deep insight on Mechanisms of chromosomal instability and carcinogenesis

Role of infections in miscarriage

Infections with certain pathogens can lead to perinatal complications. Several infections have also been associated with an increased likelihood of a miscarriage. This manuscript discusses these infections, their modes of transmission, the evidence linking them to an increased risk of miscarriage, and whether prevention or treatment strategies are available.</p

Role of infections in miscarriage

Infections with certain pathogens can lead to perinatal complications. Several infections have also been associated with an increased likelihood of a miscarriage. This manuscript discusses these infections, their modes of transmission, the evidence linking them to an increased risk of miscarriage, and whether prevention or treatment strategies are available.</p

Role of infections in miscarriage

Infections with certain pathogens can lead to perinatal complications. Several infections have also been associated with an increased likelihood of a miscarriage. This manuscript discusses these infections, their modes of transmission, the evidence linking them to an increased risk of miscarriage, and whether prevention or treatment strategies are available.</p

Merotelic attachments and non-homologous end joining are the basis of chromosomal instability

Although the large majority of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced DNA damage is brought about by uncorrected merotelic attachments, which cause kinetochore distortion, chromosome breakage at the centromere, and possible activation of DNA damage repair pathways. Although merotelic attachments are common early in mitosis, some escape detection by the kinetochore pathway. As a consequence, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. We propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis