Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes
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 <i>Apc<s...
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/6/1267 |
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| author | Vasilis S. Dionellis Maxim Norkin Angeliki Karamichali Giacomo G. Rossetti Joerg Huelsken Paloma Ordonez-Moran Thanos D. Halazonetis |
| author_facet | Vasilis S. Dionellis Maxim Norkin Angeliki Karamichali Giacomo G. Rossetti Joerg Huelsken Paloma Ordonez-Moran Thanos D. Halazonetis |
| author_sort | Vasilis S. Dionellis |
| collection | DOAJ |
| description | 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 <i>Apc<sup>lox/lox</sup></i>, <i>LSL-Kras<sup>G12D</sup></i>, and <i>Tp53<sup>lox/lox</sup></i> 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 <i>Apc</i>, <i>Kras,</i> and <i>Tp53</i> alleles had as many SNSs as tumours that expressed only mutant <i>Apc</i>. In contrast, the presence of large-scale (>10 Mb) copy number alterations (CNAs) correlated strongly with <i>Tp53</i> 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 <i>Tp53</i> 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. |
| first_indexed | 2024-03-10T13:17:17Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:17:17Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4dde6a999e13474abe7627d1108a4b0f2023-11-21T10:17:56ZengMDPI AGCancers2072-66942021-03-01136126710.3390/cancers13061267Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined GenotypesVasilis S. Dionellis0Maxim Norkin1Angeliki Karamichali2Giacomo G. Rossetti3Joerg Huelsken4Paloma Ordonez-Moran5Thanos D. Halazonetis6Department of Molecular Biology, University of Geneva, 1211 Geneva, SwitzerlandCancer Stem Cell Laboratory, Swiss Institute of Technology Lausanne (EPFL), ISREC, 1015 Lausanne, SwitzerlandDepartment of Molecular Biology, University of Geneva, 1211 Geneva, SwitzerlandDepartment of Molecular Biology, University of Geneva, 1211 Geneva, SwitzerlandCancer Stem Cell Laboratory, Swiss Institute of Technology Lausanne (EPFL), ISREC, 1015 Lausanne, SwitzerlandDivision of Cancer & Stem Cells, School of Medicine, Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UKDepartment of Molecular Biology, University of Geneva, 1211 Geneva, SwitzerlandThe 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 <i>Apc<sup>lox/lox</sup></i>, <i>LSL-Kras<sup>G12D</sup></i>, and <i>Tp53<sup>lox/lox</sup></i> 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 <i>Apc</i>, <i>Kras,</i> and <i>Tp53</i> alleles had as many SNSs as tumours that expressed only mutant <i>Apc</i>. In contrast, the presence of large-scale (>10 Mb) copy number alterations (CNAs) correlated strongly with <i>Tp53</i> 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 <i>Tp53</i> 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.https://www.mdpi.com/2072-6694/13/6/1267colorectal cancersingle cellgenomic instabilityexome sequencingmouse modelscancer drivers |
| spellingShingle | Vasilis S. Dionellis Maxim Norkin Angeliki Karamichali Giacomo G. Rossetti Joerg Huelsken Paloma Ordonez-Moran Thanos D. Halazonetis Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes Cancers colorectal cancer single cell genomic instability exome sequencing mouse models cancer drivers |
| title | Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes |
| title_full | Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes |
| title_fullStr | Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes |
| title_full_unstemmed | Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes |
| title_short | Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes |
| title_sort | genomic instability profiles at the single cell level in mouse colorectal cancers of defined genotypes |
| topic | colorectal cancer single cell genomic instability exome sequencing mouse models cancer drivers |
| url | https://www.mdpi.com/2072-6694/13/6/1267 |
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