Dionellis Vasilis S, Norkin Maxim, Karamichali Angeliki, Rossetti Giacomo G, Huelsken Joerg, Ordonez-Moran Paloma, Halazonetis Thanos D
Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland.
Cancer Stem Cell Laboratory, Swiss Institute of Technology Lausanne (EPFL), ISREC, 1015 Lausanne, Switzerland.
Cancers (Basel). 2021 Mar 12;13(6):1267. doi: 10.3390/cancers13061267.
The genomes of many human CRCs have been sequenced, revealing a large number of genetic alterations. However, the molecular mechanisms underlying the accumulation of these alterations are still being debated. In this study, we examined colorectal tumours that developed in mice with , , and targetable alleles. Organoids were derived from single cells and the spectrum of mutations was determined by exome sequencing. The number of single nucleotide substitutions (SNSs) correlated with the age of the tumour, but was unaffected by the number of targeted cancer-driver genes. Thus, tumours that expressed mutant , and alleles had as many SNSs as tumours that expressed only mutant . In contrast, the presence of large-scale (>10 Mb) copy number alterations (CNAs) correlated strongly with inactivation. Comparison of the SNSs and CNAs present in organoids derived from the same tumour revealed intratumoural heterogeneity consistent with genomic lesions accumulating at significantly higher rates in tumour cells compared to normal cells. The rate of acquisition of SNSs increased from the early stages of cancer development, whereas large-scale CNAs accumulated later, after inactivation. Thus, a significant fraction of the genomic instability present in cancer cells cannot be explained by aging processes occurring in normal cells before oncogenic transformation.
许多人类结直肠癌的基因组已被测序，揭示了大量的基因改变。然而，这些改变积累的分子机制仍存在争议。在本研究中，我们检查了在具有可靶向等位基因、和的小鼠中发生的结直肠肿瘤。类器官由单细胞衍生而来，突变谱通过外显子组测序确定。单核苷酸替换（SNS）的数量与肿瘤年龄相关，但不受靶向癌症驱动基因数量的影响。因此，表达突变、和等位基因的肿瘤与仅表达突变的肿瘤具有相同数量的SNS。相比之下，大规模（>10 Mb）拷贝数改变（CNA）的存在与失活密切相关。对来自同一肿瘤的类器官中存在的SNS和CNA进行比较，发现肿瘤内异质性与基因组损伤在肿瘤细胞中积累的速率明显高于正常细胞一致。SNS的获得速率从癌症发展的早期阶段开始增加，而大规模CNA在失活后较晚积累。因此，癌细胞中存在的很大一部分基因组不稳定性不能用致癌转化前正常细胞中发生的衰老过程来解释。
