Department of Clinical Genetics, Lund University and Skåne Regional and University Laboratories, Lund, Sweden.
PLoS One. 2013 Jul 24;8(7):e70445. doi: 10.1371/journal.pone.0070445. Print 2013.
An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours.
大多数恶性肿瘤存在染色体数目不平衡（非整倍体），这归因于染色体的有丝分裂错误分离。然而，最近的研究表明，非肿瘤性人类细胞中也存在相对较高的染色体错误分离率，而在大多数正常组织中，整个生命过程中非整倍体细胞的频率仍然较低。这意味着新形成的非整倍体细胞在健康组织中受到负向选择，而这种选择的减弱可能导致癌症中的非整倍体。为了验证这一点，我们将细胞生长建模为离散时间分支过程，在此过程中会产生染色体增益和丢失，并对其宿主细胞施加各种大小的选择压力。然后，我们实验评估了人类非肿瘤性细胞和癌细胞中染色体错误分离的频率以及非整倍体细胞的患病率。将这些数据整合到我们的模型中，可以估计单个染色体拷贝数变化导致的适合度降低，在正常细胞中平均约为 30%。相比之下，癌细胞的平均适合度降低仅为 6%（p=0.0008），表明对非整倍体的容忍。基于染色体错误分离和非整倍体容忍的共同存在的模拟重现了 >400 个癌症病例中的染色体异常分布，其保真度高于仅基于染色体错误分离的模型。通过计算机模拟对非整倍体癌细胞发育进行反向工程预测，非整倍体不耐受是限制非整倍体细胞克隆扩展的比染色体错误分离率更强的限制因素。总之，我们的研究结果表明，不仅染色体错误分离率升高，而且对新的染色体失衡的普遍容忍，也有助于人类肿瘤的基因组景观。
