Abstract
Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10−4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.
Highlights
Chromosomal instability is defined as a process of the progressive accumulation of numerical and structural chromosomal aberrations via chromosome segregation error during cell division.Chromosomal instability drives cancer initiation and evolution [1,2]
TC staining improved the detection of dicentric chromosomes with centromeres in close proximity to or in contact with the telomeres (Figure 1C)
Chromosomal instability is known to interfere with treatment responses in cancer patients and more generally with clinical outcomes in populations exposed to genotoxic agents [32]
Summary
Chromosomal instability is defined as a process of the progressive accumulation of numerical and structural chromosomal aberrations via chromosome segregation error during cell division. Chromosomal instability drives cancer initiation and evolution [1,2]. Chromosomal instability has proven to be an essential biomarker for patients with cancer, inflammatory diseases, and individuals in otherwise healthy populations exposed to genotoxic agents, as well as their progeny [3,4]. Ample evidence acquired during the past decades has demonstrated the predictive and prognostic value of chromosomal instability as a biomarker for treatment response and clinical outcomes of these populations [5,6,7,8,9,10]. Substantial progress has been achieved in the detection and identification of chromosomal instability. Conventional karyotyping involving, e.g., Giemsa banding (G and R-banding) or inverted
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