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Tumours exhibit significant heterogeneity in their molecular profiles across patients, largely influenced by the tissue of origin, where certain driver gene mutations are predominantly associated with specific cancer types. Here, we unveil an additional layer of complexity: some cancer types display anatomic location-specific mutation profiles akin to tissue-specificity. To better understand this phenomenon, we concentrate on colon cancer. While prior studies have noted changes of the frequency of molecular alterations along the colon, the underlying reasons and whether those changes occur rather gradual or are distinct between the left and right colon, remain unclear. Developing and leveraging stringent statistical models on molecular data from 522 colorectal tumours from The Cancer Genome Atlas, we reveal disparities in molecular properties between the left and right colon affecting many genes. Interestingly, alterations in genes responsive to environmental cues and properties of the tumour ecosystem, including metabolites which we quantify in a cohort of 27 colorectal cancer patients, exhibit continuous trends along the colon. Employing network methodologies, we uncover close interactions between metabolites and genes, including drivers of colon cancer, showing continuous abundance or alteration profiles. This underscores how anatomic biases in the composition and interactions within the tumour ecosystem help explaining gradients of carcinogenesis along the colon., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Martin Schaefer reports financial support was provided by AIRC Italian Foundation for Cancer Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cancers evolve under the accumulation of thousands of somatic mutations and chromosomal aberrations. While most coding mutations are deleterious, almost all protein-coding genes lack detectable signals of negative selection. This raises the question of how tumors tolerate such large amounts of deleterious mutations. Using 8,690 tumor samples from The Cancer Genome Atlas, we demonstrate that copy number amplifications frequently cover haploinsufficient genes in mutation-prone regions. This could increase tolerance towards the deleterious impact of mutations by creating safe copies of wild-type regions and, hence, protecting the genes therein. Our findings demonstrate that these potential buffering events are highly influenced by gene functions, essentiality, and mutation impact and that they occur early during tumor evolution. We show how cancer type-specific mutation landscapes drive copy number alteration patterns across cancer types. Ultimately, our work paves the way for the detection of novel cancer vulnerabilities by revealing genes that fall within amplifications likely selected during evolution to mitigate the effect of mutations., (© 2023. The Author(s).)

Summary: We present ROBUST-Web which implements our recently presented ROBUST disease module mining algorithm in a user-friendly web application. ROBUST-Web features seamless downstream disease module exploration via integrated gene set enrichment analysis, tissue expression annotation, and visualization of drug-protein and disease-gene links. Moreover, ROBUST-Web includes bias-aware edge costs for the underlying Steiner tree model as a new algorithmic feature, which allow to correct for study bias in protein-protein interaction networks and further improves the robustness of the computed modules., Availability and Implementation: Web application: https://robust-web.net. Source code of web application and Python package with new bias-aware edge costs: https://github.com/bionetslab/robust-web, https://github.com/bionetslab/robust_bias_aware., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The association between microbes and cancer has been reported repeatedly; however, it is not clear if molecular tumour properties are connected to specific microbial colonisation patterns. This is due mainly to the current technical and analytical strategy limitations to characterise tumour-associated bacteria., Methods: Here, we propose an approach to detect bacterial signals in human RNA sequencing data and associate them with the clinical and molecular properties of the tumours. The method was tested on public datasets from The Cancer Genome Atlas, and its accuracy was assessed on a new cohort of colorectal cancer patients., Results: Our analysis shows that intratumoural microbiome composition is correlated with survival, anatomic location, microsatellite instability, consensus molecular subtype and immune cell infiltration in colon tumours. In particular, we find Faecalibacterium prausnitzii, Coprococcus comes, Bacteroides spp., Fusobacterium spp. and Clostridium spp. to be strongly associated with tumour properties., Conclusions: We implemented an approach to concurrently analyse clinical and molecular properties of the tumour as well as the composition of the associated microbiome. Our results may improve patient stratification and pave the path for mechanistic studies on microbiota-tumour crosstalk., (© 2023. The Author(s).)

Codon usage influences gene expression distinctly depending on the cell context. Yet, the importance of codon bias in the simultaneous turnover of specific groups of protein-coding genes remains to be investigated. Here, we find that genes enriched in A/T-ending codons are expressed more coordinately in general and across tissues and development than those enriched in G/C-ending codons. tRNA abundance measurements indicate that this coordination is linked to the expression changes of tRNA isoacceptors reading A/T-ending codons. Genes with similar codon composition are more likely to be part of the same protein complex, especially for genes with A/T-ending codons. The codon preferences of genes with A/T-ending codons are conserved among mammals and other vertebrates. We suggest that this orchestration contributes to tissue-specific and ontogenetic-specific expression, which can facilitate, for instance, timely protein complex formation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Codon usage and nucleotide composition of coding sequences have profound effects on protein expression. However, while it is recognized that different tissues have distinct tRNA profiles and codon usages in their transcriptomes, the effect of tissue-specific codon optimality on protein synthesis remains elusive., Results: We leverage existing state-of-the-art transcriptomics and proteomics datasets from the GTEx project and the Human Protein Atlas to compute the protein-to-mRNA ratios of 36 human tissues. Using this as a proxy of translational efficiency, we build a machine learning model that identifies codons enriched or depleted in specific tissues. We detect two clusters of tissues with an opposite pattern of codon preferences. We then use these identified patterns for the development of CUSTOM, a codon optimizer algorithm which suggests a synonymous codon design in order to optimize protein production in a tissue-specific manner. In human cell-line models, we provide evidence that codon optimization should take into account particularities of the translational machinery of the tissues in which the target proteins are expressed and that our approach can design genes with tissue-optimized expression profiles., Conclusions: We provide proof-of-concept evidence that codon preferences exist in tissue-specific protein synthesis and demonstrate its application to synthetic gene design. We show that CUSTOM can be of benefit in biological and biotechnological applications, such as in the design of tissue-targeted therapies and vaccines., (© 2023. The Author(s).)

Transfer RNA (tRNA) utilizes multiple properties of abundance, modification, and aminoacylation in translational regulation. These properties were typically studied one-by-one; however, recent advance in high throughput tRNA sequencing enables their simultaneous assessment in the same sequencing data. How these properties are coordinated at the transcriptome level is an open question. Here, we develop a single-read tRNA analysis pipeline that takes advantage of the pseudo single-molecule nature of tRNA sequencing in NGS libraries. tRNAs are short enough that a single NGS read can represent one tRNA molecule, and can simultaneously report on the status of multiple modifications, aminoacylation, and fragmentation of each molecule. We find correlations among modification-modification, modification-aminoacylation and modification-fragmentation. We identify interdependencies among one of the most common tRNA modifications, m1A58, as coordinators of tissue-specific gene expression. Our method, SingLe-read Analysis of Crosstalks (SLAC), reveals tRNAome-wide networks of modifications, aminoacylation, and fragmentation. We observe changes of these networks under different stresses, and assign a function for tRNA modification in translational regulation and fragment biogenesis. SLAC leverages the richness of the tRNA-seq data and provides new insights on the coordination of tRNA properties., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

CD8 + T cells are a major prognostic determinant in solid tumors, including colorectal cancer (CRC). However, understanding how the interplay between different immune cells impacts on clinical outcome is still in its infancy. Here, we describe that the interaction of tumor infiltrating neutrophils expressing high levels of CD15 with CD8 + T effector memory cells (T EM ) correlates with tumor progression. Mechanistically, stromal cell-derived factor-1 (CXCL12/SDF-1) promotes the retention of neutrophils within tumors, increasing the crosstalk with CD8 + T cells. As a consequence of the contact-mediated interaction with neutrophils, CD8 + T cells are skewed to produce high levels of GZMK, which in turn decreases E-cadherin on the intestinal epithelium and favors tumor progression. Overall, our results highlight the emergence of GZMK high CD8 + T EM in non-metastatic CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics., (© 2022. The Author(s).)

Aneuploidy, a state of chromosome imbalance, is a hallmark of human tumors, but its role in cancer still remains to be fully elucidated. To understand the consequences of whole-chromosome-level aneuploidies on the proteome, we integrated aneuploidy, transcriptomic, and proteomic data from hundreds of The Cancer Genome Atlas/Clinical Proteomic Tumor Analysis Consortium tumor samples. We found a surprisingly large number of expression changes happened on other, non-aneuploid chromosomes. Moreover, we identified an association between those changes and co-complex members of proteins from aneuploid chromosomes. This co-abundance association is tightly regulated for aggregation-prone aneuploid proteins and those involved in a smaller number of complexes. On the other hand, we observed that complexes of the cellular core machinery are under functional selection to maintain their stoichiometric balance in aneuploid tumors. Ultimately, we provide evidence that those compensatory and functional maintenance mechanisms are established through post-translational control, and that the degree of success of a tumor to deal with aneuploidy-induced stoichiometric imbalance impacts the activation of cellular protein degradation programs and patient survival., Competing Interests: GS, SS, MS No competing interests declared, (© 2022, Senger et al.)

While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)