The co-evolution of the genome and epigenome in colorectal cancer

Heide, Timon; Househam, Jacob; Cresswell, George D; Spiteri, Inmaculada; Lynn, Claire; Mossner, Max; Kimberley, Chris; Fernandez-Mateos, Javier; Chen, Bingjie; Zapata, Luís; James, Chela; Barozzi, Iros; Chkhaidze, Ketevan; Nichol, Daniel; Berner, Alison; Schmidt, Melissa; Lakatos, Eszter; Baker, Ann‐Marie; Costa, Helena; Mitchinson, Miriam; Jansen, Marnix; Caravagna, Giulio; Ramazzotti, Daniele; Shibata, Darryl; Bridgewater, John; Rodriguez‐Justo, Manuel; Magnani, Luca; Graham, Trevor A.; Sottoriva, Andrea

doi:10.1101/2021.07.12.451121

Cited by 3 publications

(1 citation statement)

References 109 publications

(138 reference statements)

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“…Single-cell RNA-Seq suggested that the ISG signature observed correlated with chromatin status in Mre11 ATLD1/ATLD1 organoids. To visualize chromatin status and ISG signature simultaneously at single-cell level, expression levels of 113 chromatin modifiers and remodelers examined in a previous study 39 were used as a proxy of chromatin status. Potential of Heat-diffusion for Affinity-based Trajectory Embedding (PHATE) analysis was performed, which was then color-coded by ISG signature score.…”

Section: The Differential Responses and Increased Tumorigenesis In Ne...mentioning

confidence: 99%

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

Wang,

Canasto-Chibuque,

Kim

et al. 2023

Preprint

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The Mre11 complex (comprising Mre11, Rad50, Nbs1) is integral to the maintenance of genome stability. We previously showed that a hypomorphicMre11mutant mouse strain (Mre11ATLD1/ATLD1) was highly susceptible to oncogene induced breast cancer. Here we used a mammary organoid system to examine which Mre11 dependent responses are tumor suppressive. We found thatMre11ATLD1/ATLD1organoids exhibited an elevated interferon stimulated gene (ISG) signature and sustained changes in chromatin accessibility. ThisMre11ATLD1/ATLD1phenotype depended on DNA binding of a nuclear innate immune sensor, IFI205. Ablation ofIfi205inMre11ATLD1/ATLD1organoids restored baseline and oncogene-induced chromatin accessibility patterns to those observed inWT. Implantation ofMre11ATLD1/ATLD1organoids and activation of oncogene led to aggressive metastatic breast cancer. This outcome was reversed in implantedIfi205-/-Mre11ATLD1/ATLD1organoids. These data reveal a connection between innate immune signaling and tumor suppression in mammary epithelium. Given the abundance of aberrant DNA structures that arise in the context of genome instability syndromes, the data further suggest that cancer predisposition in those contexts may be partially attributable to tonic innate immune transcriptional programs.

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Section: The Differential Responses and Increased Tumorigenesis In Ne...mentioning

confidence: 99%

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

Wang,

Canasto-Chibuque,

Kim

et al. 2023

Preprint

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Machine learning-based meta-analysis of colorectal cancer and inflammatory bowel disease

Usefi

Sardari

2023

Preprint

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Colorectal cancer (CRC) is a major global health concern, resulting in numerous cancer-related deaths. CRC detection, treatment, and prevention can be improved by identifying genes and biomarkers. Despite extensive research, the underlying mechanisms of CRC remain elusive, and previously identified biomarkers have not yielded satisfactory insights. This shortfall may be attributed to the predominance of univariate analysis methods, which overlook potential combinations of variants and genes contributing to disease development. Here, we address this knowledge gap by presenting a novel multivariate machine-learning strategy to pinpoint genes associated with CRC. Additionally, we applied our analysis pipeline to Inflammatory Bowel Disease (IBD), as IBD patients face substantial CRC risk. The importance of the identified genes was substantiated by rigorous validation across numerous independent datasets. Several of the discovered genes have been previously linked to CRC, while others represent novel findings warranting further investigation.

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An Epigenetic LINE-1-Based Mechanism in Cancer

Lavia

Sciamanna

Spadafora

2022

IJMS

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In the last fifty years, large efforts have been deployed in basic research, clinical oncology, and clinical trials, yielding an enormous amount of information regarding the molecular mechanisms of cancer and the design of effective therapies. The knowledge that has accumulated underpins the complexity, multifactoriality, and heterogeneity of cancer, disclosing novel landscapes in cancer biology with a key role of genome plasticity. Here, we propose that cancer onset and progression are determined by a stress-responsive epigenetic mechanism, resulting from the convergence of upregulation of LINE-1 (long interspersed nuclear element 1), the largest family of human retrotransposons, genome damage, nuclear lamina fragmentation, chromatin remodeling, genome reprogramming, and autophagy activation. The upregulated expression of LINE-1 retrotransposons and their protein products plays a key role in these processes, yielding an increased plasticity of the nuclear architecture with the ensuing reprogramming of global gene expression, including the reactivation of embryonic transcription profiles. Cancer phenotypes would thus emerge as a consequence of the unscheduled reactivation of embryonic gene expression patterns in an inappropriate context, triggering de-differentiation and aberrant proliferation in differentiated cells. Depending on the intensity of the stressing stimuli and the level of LINE-1 response, diverse degrees of malignity would be generated.

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The co-evolution of the genome and epigenome in colorectal cancer

Cited by 3 publications

References 109 publications

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

Chronic Interferon Stimulated Gene Transcription Promotes Oncogene Induced Breast Cancer

Machine learning-based meta-analysis of colorectal cancer and inflammatory bowel disease

An Epigenetic LINE-1-Based Mechanism in Cancer

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