Whole chromosome gain does not in itself confer cancer-like chromosomal instability

Abstract

Constitutional aneuploidy is typically caused by a single-event meiotic or early mitotic error. In contrast, somatic aneuploidy, found mainly in neoplastic tissue, is attributed to continuous chromosomal instability. More debated as a cause of aneuploidy is aneuploidy itself; that is, whether aneuploidy per se causes chromosomal instability, for example, in patients with inborn aneuploidy. We have addressed this issue by quantifying the level of somatic mosaicism, a proxy marker of chromosomal instability, in patients with constitutional aneuploidy by precise backgroundfiltered dual-color FISH. In contrast to previous studies that used less precise methods, we find that constitutional trisomy, even for large chromosomes that are often trisomic in cancer, does not confer a significantly elevated rate of somatic chromosomal mosaicism in individual cases. Constitutional triploidy was associated with an increased level of somatic mosaicism, but this consisted mostly of reversion from trisomy to disomy and did not correspond to a proportionally elevated level of chromosome mis-segregation in triploids, indicating that the observed mosaicism resulted from a specific accumulation of cells with a hypotriploid chromosome number. In no case did the rate of somatic mosaicism in constitutional aneuploidy exceed that of "chromosomally stable" cancer cells. Our findings show that even though constitutional aneuploidy was in some cases associated with low-level somatic mosaicism, it was insufficient to generate the cancer-like levels expected if aneuploidy single-handedly triggered cancer-like chromosomal instability.neoplasia | Down syndrome | Edwards syndrome | Patau syndrome

Does aneuploidy destabilize karyotypes automatically?

“…The fact that the two triploid cases of Valind et al (1) developed sufficiently for cytogenetic analysis, while others described previously were even born alive (6) confirms this prediction. Nevertheless, a threefold polyploidy is still likely to unbalance gene teams optimized for diploidy, as the higher-than-normal instability of the two triploids suggests.…”

“…. cancer-like chromosomal instability" (1). It would seem, therefore, that the new data of Valind et al support the concept that chromosomal instability is directly proportional to the degree of aneuploidy.…”

“…In their recent paper, Valind et al test the theory that "aneuploidy automatically" destabilizes the karyotype (1). According to this theory, aneuploidy, an abnormal balance of chromosomes, destabilizes the karyotype automatically by unbalancing the cooperations of thousands of genes, especially mitosis genes: The more aneuploid the cell the more unstable is the karyotype (2)(3)(4)(5).…”

CIN and Aneuploidy: Different Concepts, Different Consequences

“…[17] However, in fully triploid fibroblasts (three copies of each chromosome) the percentage of aneuploid cells increases, but the rate of chromosome mis-segregation (CIN), relative to a euploid control, does not. [6] This can be explained by the fact that triploid cells that encountered chromosome losses had a growth advantage relative to their fully triploid counterparts, whereas chromosome losses were selected against in the diploid cells; this shows that the increased rate of aneuploidy was due to selection, not an increased CIN rate. Additionally, while aneuploidy was shown to lead to increased CIN in the short term, it remains to be seen whether the resulting additional aneuploidies remain present long-term.…”

“…One of the most wellknown examples of aneuploidy without CIN is Down syndrome, caused by systemic trisomy of chromosome 21; these cells are aneuploid without an increased mis-segregation rate. [6] Additionally, stable aneuploid cell lines have been engineered by introducing one or more extra chromosomes to investigate the consequences of aneuploidy in the absence of CIN. [7,8] There are many methods to quantify aneuploidy, [9] but in order to quantify CIN actual mis-segregation rates need to be measured in living cells, which is time consuming and challenging, especially in animal models.…”