Genomic instability profiles at the single cell level in mouse colorectal cancers of defined genotypes

Dionellis, Vasilis S.; Norkin, Maxim; Karamichali, Angeliki; Rossetti, Giacomo G.; Huelsken, Joerg; Ordonez-Moran, Paloma; Halazonetis, Thanos D.

Abstract

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 Apclox/lox, LSL-KrasG12D, and Tp53lox/lox 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 Apc, Kras, and Tp53 alleles had as many SNSs as tumours that expressed only mutant Apc. In contrast, the presence of large-scale (>10 Mb) copy number alterations (CNAs) correlated strongly with Tp53 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 Tp53 inacti-vation. 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.

Citation

Dionellis, V. S., Norkin, M., Karamichali, A., Rossetti, G. G., Huelsken, J., Ordonez-Moran, P., & Halazonetis, T. D. (2021). Genomic instability profiles at the single cell level in mouse colorectal cancers of defined genotypes. Cancers, 13(6), Article 1267. https://doi.org/10.3390/cancers13061267

• Journal Article Type: Article
• Acceptance Date: Mar 9, 2021
• Online Publication Date: Mar 12, 2021
• Publication Date: Mar 12, 2021
• Deposit Date: Jun 24, 2021
• Publicly Available Date: Jun 25, 2021
• Journal: Cancers
• Electronic ISSN: 2072-6694
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 6
• Article Number: 1267
• DOI: https://doi.org/10.3390/cancers13061267
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/5721897
• Publisher URL: https://www.mdpi.com/2072-6694/13/6/1267