Department of Clinical Genetics, Lund University, University and Regional Laboratories, Biomedical Center B13, Lund SE22184, Sweden.
Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):21119-23. doi: 10.1073/pnas.1311163110. Epub 2013 Dec 9.
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 background-filtered 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.
染色体非整倍性通常是由单个减数分裂或早期有丝分裂错误引起的。相比之下，主要存在于肿瘤组织中的体染色体非整倍性归因于连续的染色体不稳定性。作为非整倍体的一个原因更有争议的是本身的非整倍体；也就是说，非整倍体本身是否会导致染色体不稳定性，例如在先天性非整倍体患者中。我们通过精确背景过滤的双色 FISH 定量分析了染色体不稳定性的替代标志物——体细胞镶嵌性，从而解决了这个问题。与之前使用不精确方法的研究相比，我们发现即使对于在癌症中经常三体的大染色体，染色体非整倍体也不会导致个体病例中体细胞染色体镶嵌性的显著升高率。染色体三体性与体细胞镶嵌性水平升高有关，但这主要由三体向二体的回复组成，与三体中染色体错误分离的比例升高不对应，表明观察到的镶嵌性是由于低倍体染色体数的细胞特定积累所致。在染色体非整倍体的情况下，体细胞镶嵌率从未超过“染色体稳定”癌细胞的水平。我们的研究结果表明，尽管在某些情况下染色体非整倍体与低水平的体细胞镶嵌性有关，但不足以产生如果非整倍体单独引发类似癌症的染色体不稳定性，则预期的类似癌症的水平。
