Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes

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 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.

Integrating bulk and single-cell RNA sequencing data reveals epithelial-mesenchymal transition molecular subtype and signature to predict prognosis, immunotherapy efficacy, and drug candidates in low-grade gliomas

“…Genomic instability is a hallmark of cancer, particularly LGG, which facilitates its growth and the ability to withstand treatments ( Dionellis et al, 2021 ). In our result, we found that Aneuploidy score, fraction altered, number of segments, tumor mutation burden (TMB) were elevated in C2, while Cancer Testicular Antigens (CTA) score were lower in C2, which consistent with previously reports ( Nie et al, 2020 ) ( Figure 6 ).…”

“…We further checked the expression of immune checkpoint between groups and found that the genes showed a high expression level in high risk group ( Figure 9B ). Accumulative evidence have demonstrated that anti-tumor effects of a high T cell infiltration are counteracted by the immunosuppressive pathways that are triggered by the over-expression of immune checkpoint proteins ( Vuong et al, 2019 ; Dionellis et al, 2021 ). The GSEA analysis was performed between groups, and found cell cycle, chemokine signaling pathway, cytokine-cytokine receptor interaction, ECM receptor interaction, p53 signaling pathway were significantly enriched in high risk group ( Figure 9C ).…”

“…The result of Figure 9A revealed that most of immune cells infiltration level in high risk group were elevated compared to low risk group, such as Activated CD8 + T cells (CD8 + Ta), effector memory CD4 + T cells, Regulatory T cells, CD56bright natural Killer cells, Type-1 T-helper 1 cells, Central memory CD4 + T cells, Activated We further checked the expression of immune checkpoint between groups and found that the genes showed a high expression level in high risk group (Figure 9B). Accumulative evidence have demonstrated that anti-tumor effects of a high T cell infiltration are counteracted by the immunosuppressive pathways that are triggered by the overexpression of immune checkpoint proteins (Vuong et al, 2019;Dionellis et al, 2021). The GSEA analysis was performed between groups, and found cell cycle, chemokine signaling pathway, cytokine-cytokine receptor interaction, ECM receptor interaction, p53 signaling pathway were significantly enriched in high risk group (Figure 9C).…”

Prognostic prediction and immunotherapy response analysis of the fatty acid metabolism-related genes in clear cell renal cell carcinoma

“…Herein, we found that high-risk patients were more sensitive to bortezomib, gefitinib, and temsirolimus than other treatments, indicating that they might benefit from chemotherapy. The significant genomic heterogeneity differences between the groups reflect features of tumor promotion and treatment resistance in the high-risk group, highlighting the importance of immunotherapy in ccRCC [ 106 ]. Therefore, we explored immunotherapy responses between the low- and high-risk groups and found that the characteristics reflecting the immunotherapy response were increased in the high-risk group compared to the low-risk group.…”

Identification of a Somatic Mutation-Derived Long Non-Coding RNA Signatures of Genomic Instability in Renal Cell Carcinoma

“…Genomic instability plays a key role in the development of cancer. For example, structural changes in proto-oncogenes and tumor suppressor genes may lead to abnormalities in cell functions, including cell growth, cell cycle, cell senescence and apoptosis, cell invasion and metastasis (15)(16)(17)(18). The genomic instabilities of cancer mainly include gene mutation, chromosome rearrangement and aneuploidy (19).…”