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The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability.

ABSTRACT: Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles. By investigating the impact of monosomies, trisomies and segmental aneuploidies on chromosomal instability we further deciphered the complex relationship between aneuploidy and CIN.

SUBMITTER: Hintzen DC

PROVIDER: S-EPMC9249180 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability.

Hintzen Dorine C DC Soto Mar M Schubert Michael M Bakker Bjorn B Spierings Diana C J DCJ Szuhai Karoly K Lansdorp Peter M PM Kluin Roel J C RJC Foijer Floris F Medema René H RH Raaijmakers Jonne A JA

PloS one 20220701 7

Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploi ...[more]

PMID: 35776704

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Project description:In briefWhether sperm DNA fragmentation (SDF) affects embryo development and clinical outcomes is still controversial, which limits the utility of SDF testing in assisted reproductive technology management. This study demonstrates that high SDF is associated with the incidence of segmental chromosomal aneuploidy and increased paternal whole chromosomal aneuploidies.AbstractWe aimed to investigate the correlation of sperm DNA fragmentation (SDF) with the incidence and paternal origin of whole and segmental chromosomal aneuploidies of embryos at the blastocyst stage. A retrospective cohort study was conducted with a total of 174 couples (women aged 35 years or younger) who underwent 238 cycles (including 748 blastocysts) of preimplantation genetic testing for monogenic diseases (PGT-M). All subjects were divided into two groups based on the sperm DNA fragmentation index (DFI) level: low DFI (<27%) and high DFI (≥27%). The rates of euploidy, whole chromosomal aneuploidy, segmental chromosomal aneuploidy, mosaicism, parental origin of aneuploidy, fertilization, cleavage, and blastocyst formation were compared between low- and high-DFI groups. We found no significant differences in fertilization, cleavage, or blastocyst formation between the two groups. Compared to that in the low-DFI group, segmental chromosomal aneuploidy rate was significantly higher in the high-DFI group (11.57% vs 5.83%, P = 0.021; OR: 2.32, 95% CI: 1.10-4.89, P = 0.028). The whole chromosomal embryonic aneuploidy of paternal origin was significantly higher in cycles with high DFI than in cycles with low DFI (46.43% vs 23.33%, P = 0.018; OR: 4.32, 95% CI: 1.06-17.66, P = 0.041). However, the segmental chromosomal aneuploidy of paternal origin was not significantly different between the two groups (71.43% vs 78.05%, P = 0.615; OR: 1.01, 95% CI: 0.16-6.40, P = 0.995). In conclusion, our results suggested that high SDF was associated with the incidence of segmental chromosomal aneuploidy and increased paternal whole chromosomal aneuploidies in embryos.

Project description:BackgroundChromosome abnormalities, especially trisomy of chromosome 21, 13, or 18 as well as sex chromosome aneuploidy, are a well-established cause of pregnancy loss. Cultured cell karyotype analysis and FISH have been considered reliable detectors of fetal abnormality. However, results are usually not available for 3-4 days or more. Multiplex ligation-dependent probe amplification (MLPA) has emerged as an alternative rapid technique for detection of chromosome aneuploidies. However, conventional MLPA does not allow for relative quantification of more than 50 different target sequences in one reaction and does not detect mosaic trisomy. A multiplexed MLPA with more sensitive detection would be useful for fetal genetic screening.MethodsWe developed a method of array-based MLPA to rapidly screen for common aneuploidies. We designed 116 universal tag-probes covering chromosomes 13, 18, 21, X, and Y, and 8 control autosomal genes. We performed MLPA and hybridized the products on a 4-well flow-through microarray system. We determined chromosome copy numbers by analyzing the relative signals of the chromosome-specific probes.ResultsIn a blind study of 161 peripheral blood and 12 amniotic fluid samples previously karyotyped, 169 of 173 (97.7%) including all the amniotic fluid samples were correctly identified by array-MLPA. Furthermore, we detected two chromosome X monosomy mosaic cases in which the mosaism rates estimated by array-MLPA were basically consistent with the results from karyotyping. Additionally, we identified five Y chromosome abnormalities in which G-banding could not distinguish their origins for four of the five cases.ConclusionsOur study demonstrates the successful application and strong potential of array-MLPA in clinical diagnosis and prenatal testing for rapid and sensitive chromosomal aneuploidy screening. Furthermore, we have developed a simple and rapid procedure for screening copy numbers on chromosomes 13, 18, 21, X, and Y using array-MLPA.

Dataset Information

The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability.

Publications

The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability.

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