Biology subjects

West, C.

Publications and source records attributed to West, C..

16 recordsLinked to original sources

bioRxiv2026

Oxygen-sensing regulatory architecture structures mammalian diversification

The HIF oxygen-sensing pathway traces to the last metazoan common ancestor [~]800 million years ago and is conventionally viewed as a conserved cellular stress-response module. Whether this ancestral system has contributed to mammalian diversification at macroevolutionary timescales remains unexplored. We analyzed sequence-encoded TF-gene regulatory architecture for 34 transcription factors and 705 genes in 10 oxygen-sensing pathways across 239 mammalian species. Oxygen-sensing regulatory architecture carries strong clade-structured evolutionary signal. The primary axis of variation tracks a fast-slow life history gradient, marked by rewiring of growth-control and tumor suppressor hub genes. A second axis recovers the monotreme-marsupial-placental transition and aligns with the decline in atmospheric O2 from the Permo-Carboniferous maximum toward present-day levels1. Orthogonal axes encode distinct ecological regulatory strategies; two later axes separately resolve HIF-compatible binding-site architecture and dominant TF-family assignment, identifying regulatory strategies associated with powered flight and hibernation. This multidimensional space also informs Petos paradox, suggesting that relative cancer resistance tracks the combination of tumor-suppressor enrichment and coordinated HIF-complex assignment. Together, these results indicate that regulatory configurations arise at major evolutionary transitions and persist coherently across descendant lineages through a punctuated mode of regulatory evolution, providing genomic-level evidence for Simpsons adaptive zones and a mechanism for evolutionary stasis. These findings reframe oxygen sensing as a regulatory hub in mammalian diversification, with stable patterns of TF-family assignment configurations emerging as a structuring force in macroevolution. BriefAncient molecular processes such as oxygen-sensing, whose HIF-pathway dates to the origin of animals [~]800 million years ago, are typically regarded as conserved across lineages. How such deeply ancestral systems have contributed to mammalian diversification remains largely unexplored. By analyzing the oxygen-sensing regulatory architecture (which transcription factors regulate which genes) across 239 mammalian species, we find that oxygen-sensing regulatory rewiring tracks placental evolution, atmospheric O2, life history evolution, ecological specializations, and cancer resistance. Major radiations occupy discrete, heritable configurations established at key phylogenetic transitions and subsequently retained across descendant lineages through near-neutral within-regime drift, revealing regulatory architecture lock-in as a structuring force in macroevolution.

evolutionary biology↗

bioRxiv2026

Whole-genome pre-amplification as a viable approach for genomic screening of FFPE-derived DNA samples

Whole-genome sequencing (WGS) enables comprehensive analysis of tumour genomes, but its use in formalin-fixed paraffin-embedded (FFPE) samples is limited by DNA fragmentation and low yields. Whole-genome amplification (WGA) methods such as multiple displacement amplification (MDA) can boost DNA availability but distort copy-number alteration (CNA) profiles. DNA ligation-mediated MDA (DLMDA) mitigates this bias by reconstituting fragmented templates, yet its performance in FFPE-derived DNA remains uncertain. We compared paired DLMDA pre-amplified (2h, 8h) and non-pre-amplified FFPE prostate tumour samples from 22 archival blocks (5, 15 and 20 years old). DLMDA increased DNA yield by 42- to 86-fold, with global CNA patterns largely preserved. However, DLMDA significantly reduced the number of detected CNA deletions and amplifications. These effects were independent of both block age and reaction time. CNA dropouts were randomly distributed across the genome, indicating that DLMDA does not introduce regional bias. Our results show that DLMDA enables robust DNA yield recovery and avoids false-positive CNA artefacts, but at the cost of reduced CNA sensitivity. While suitable for CNA screening pipelines through WGS, further improvements are required to minimise the false-negative risk and improve the techniques sensitivity for FFPE-based genomics.

molecular biology↗

bioRxiv2026

Genes near tRNAs are enriched in translational machinery

Transfer RNAs (tRNAs) are known for delivering amino acids to the growing polypeptide chain during translation. They can also influence gene expression, especially in times of nutrient starvation, through differential tRNA expression and modification. tRNAs have a highly consistent cloverleaf structure, but relatively few known regulatory elements govern this conserved structure despite the 20 different standard isotypes. This study examines gene enrichment patterns near tRNA in 1154 fungal genomes. Genes enriched in proteasome regulation, ion transport, and rRNA were found to be significantly closer to tRNAs than other pathways. These results were consistent across KEGG over-representation analysis (ORA), KEGG Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO) analysis. Proteasome, ion transport, and RNA are all important aspects of protein production and regulation, suggesting that genes required for the synthesis and quality control of proteins, including tRNAs, are located near each other. Protein regulation is an energetically expensive process, and local co-regulation could increase efficiency and stress impacts on proteins.

bioinformatics↗

bioRxiv2025

Comparative genomics reveals multipartite genomes undergoing loss in the fungal endosymbiotic genus Mycetohabitans

Endosymbiotic bacteria extensively impact phenotypes of their eukaryotic hosts, while experiencing dramatic changes to their own genome as they become more host-restricted in lifestyle. Understanding the trajectory of such a genome has largely been done through study of animal-associated bacteria, especially insect endosymbionts. Yet, endofungal bacteria provide another natural experimental model for investigating how microbial genomes change when living inside of a host cell. Mycetohabitans spp. are culturable bacterial endosymbionts of the Mucoromycota fungus Rhizopus microsporus. To investigate the genome dynamics resulting from the endohyphal nature of this emerging model genus, we long-read sequenced and assembled new complete genomes to combine with previous assemblies, creating a global dataset of 28 complete Mycetohabitans genomes. All genomes were between 3.3 and 3.9 Mbp in size and were multipartite, structured into two conserved replicons with some strains having an additional plasmid. Based on evolutionary rate and gene content analysis of the different replicons, we termed the two major ones a chromosome and chromid. The differential presence of a third, mobilome-rich plasmid in some strains and the proliferation of transposable elements provide putative mechanisms for recombination or gene loss. The conservation of intact prophage and putative toxin-antitoxin systems, and extensive enrichment of secondary metabolite clusters in the Mycetohabitans genomes highlight the dynamic nature of this reducing genome. With fungal-bacterial symbioses becoming increasingly apparent phenomena, lessons learned from this symbiosis will inform our understanding of bacterial adaptation to novel hosts, and the process of microbe-microbe coevolution. SIGNIFICANCEGenomes change when organisms become closely associated, as bacterial partners undergo less opportunities for genetic exchange and become more reliant on their hosts. Our pangenome analysis of the endofungal genus Mycetohabitans shows a snapshot of evolution where the bacteria are moving from a facultative towards an obligate relationship with their host fungi. We find that Mycetohabitans genomes are marked by transposable elements, pseudogenes, a large biosynthetic repertoire, and novel bacteriophage. We provide a genomic resource to match publicly accessible strains for future work on endosymbiotic genetics and evolution.

genomics↗

bioRxiv2025

Assessing Large Language Model Alignment Towards Radio-logical Myths and Misconceptions

Background/ObjectivesTopics in radiation, such as radiology and nuclear energy usage, are rife with speculation, opinion, and misconception, posing potential risks to public health and safety if misunderstandings are left uncorrected. Achieving objective and unbiased discussion is therefore critical for advancing the field of radiation protection and ensuring that policy, research, and clinical practices are guided by accurate information. Moreover, the increased adoption of AI and large language models in recent times has necessitated an investigation into AI sentiment towards radiological topics, as well as the usage of AI in analyzing or affecting this sentiment. MethodsA systematic framework was developed to extract agreement and sentiment towards radiological ideas in a structured format. Using this method, we test several large language models, primarily OpenAIs GPT class of models, on their susceptibility to common radiological myths and mis-conceptions, their cultural and linguistic bias towards controversial radiological topics, and their philosophical/moral alignment in various radiation scenarios. We also use large OpenAIs GPT 4o mini as a tool to analyze community sentiment towards radiation in the /r/Radiation subreddit from February 2021 to December 2023. Finally, a novel AntiRadiophobeGPT is created to counter radiophobic and myth-containing rhetoric, which is then deployed and evaluated against actual user comments. ResultsIt is found that GPT 4o mini is more susceptible to overt agreement with controversial radiological views or myths/misconceptions compared to GPT 4o. As well, the use of smaller models and/or Chinese-language prompts or models significantly increases model bias towards a cultural controversial radiological topic. All GPT-class models tested for moral alignment show deontological leanings, although there is some variance in per-scenario utilitarianism. Our analysis of the radiation subreddit reveals that health-related myths are the most prevalent, but that overall community-wide myth prevalence, radiophobia and hostility have significantly decreased over the 3-year period analyzed. Finally, our custom AntiRadiophobeGPT is shown to provide responses which address radiological myths and misconceptions with a high level of truthfulness but with significantly less hostility and radiophobia compared to actual users. ConclusionsOur findings demonstrate that large language models can detect and counter radiological myths while also exhibiting vulnerabilities to similar misconceptions. By monitoring community sentiment and deploying targeted anti-misinformation tools, these models can strengthen public understanding of radiation and reduce harmful radiophobia. While AntiRadiophobeGPT shows promise in correcting misconceptions, its deployment must be approached with caution and robust oversight to safeguard against unintended manipulations and ensure responsible public discourse. This duality underscores both the potential and limitations in enhancing radiation protection strategies with LLMs. Simple SummaryHumans are susceptible to believing in or espousing myths and misconceptions in the radiological field. Since the advent of large language models (LLMs)--with applications such as ChatGPT processing over one billion queries per day, and Gemini now integrated into Googles search engine--these models have steadily evolved into a major source of information for vast audiences. The aim of our study was to assess whether large language models, which are primarily trained on human-generated data, are susceptible to the same underlying sentiments and biases with regards to radiological topics. Furthermore, we assess the use of large language models in both detecting and analyzing trends in the circulation of radiological myths and misconceptions in online communities. Finally, we evaluate the use of large language models as supportive tools for improving communication on these controversial topics.

bioinformatics↗

bioRxiv2025

Fractionated radiation alters the extracellular matrix produced by muscle-invasive bladder cancer cells

Muscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but has not been studied in MIBC. Here we aimed to characterise the impact of radiation on the ECM composition of MIBC. Materials and MethodsThree MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer cells and immunofluorescence to investigate changes in the morphology and number of ECM fibres. We evaluated the RNA expression of identified ECM proteins (FN1, COL5A1, COL1A1, TNF6AIP6, FLG) in one cystectomy (TCGA-BLCA, n=397) and two radiotherapy (BC2001, n=313; BCON, n=151) cohorts. ResultsThere were 613 proteins affected by radiation (padj<0.05, fold change >2 or <-2), 68 of which were ECM-associated proteins. There was a general increase in proteases and protease regulators but heterogeneity across cell lines. Enrichment analysis showed ECM organisation was the primary pathway affected. Immunofluorescence confirmed radiation affected ECM structure, generally, reducing the number, length and width of fibres. High FN1, COL5A1, COL1A1, TNF6AIP6 and FLG mRNA levels were adverse prognostic markers in clinical cohorts. ConclusionRadiation alters the composition and structure of the ECM produced by MIBC. As a proof-of-concept, we showed the expression of radiation-affected ECM genes are prognostic markers in MIBC. Future studies should validate these radiation-induced ECM changes in clinical samples.

cancer biology↗

bioRxiv2025

Hypoxia-induced extracellular matrix changes are conserved in cancer and directly impact radiotherapy benefit

Our overarching aim was to determine how hypoxia affects the extracellular matrix (ECM). Transcriptomic analysis (21,941 patients; 10 cancer types) identified ECM remodelling as the predominant pathway affected by hypoxia. Multi-omics confirmed that hypoxia impacts ECM organisation and collagen degradation; 53 ECM genes were affected, of which 74% were HIF1/HIF2-regulated. Spatial transcriptomics highlighted different hypoxia remodelling processes in tumour and stroma. Five ECM genes commonly affected in tumour and in vitro constituted a signature. This signature was independently prognostic and independently predictive of radiotherapy benefit in multiple malignancies. Patients within either high or low hypoxic-ECM score tertiles benefited from radiotherapy versus surgery. Hypoxic ECMs generated in vitro increased adhesion and decreased migration of cancer cells, an effect enhanced by irradiation. Immunofluorescence demonstrated that hypoxia decreased collagen fibre number, and irradiation decreased cell-ECM interactions. Taken together, these findings demonstrate hypoxia induces pan-cancer ECM changes, directly impacting radiotherapy benefit.

cancer biology↗

bioRxiv2025

Genomic factors limiting the diversity of Saccharomycotina plant pathogens

The Saccharomycotina fungi have evolved to inhabit a vast diversity of habitats over their 400-million-year evolution. There are, however, only a few known fungal pathogens of plants in this subphylum, primarily belonging to the genera Eremothecium and Geotrichum. We compared the genomes of 12 plant-pathogenic Saccharomycotina strains to 360 plant-associated strains to identify features unique to the phytopathogens. Characterization of the oxylipin synthesis genes, a compound believed to be involved in Eremothecium pathogenicity, did not reveal any differences in gene presence within or between the plant-pathogenic and plant-associated strains. A reverse-ecological approach, however, revealed that plant pathogens lack several metabolic enzymes known to assist other phytopathogens in overcoming plant defenses. This includes L-rhamnose metabolism, formamidase and nitrilase genes. This result suggests that the Saccharomycotina plant pathogens are limited to infecting ripening fruits as they are without the necessary enzymes to degrade common phytohormones and secondary metabolites produced by plants.

genomics↗

bioRxiv2024

Detecting interspecific positive selection using convolutional neural networks

Traditional statistical methods using maximum likelihood and Bayesian inference can detect positive selection from an interspecific phylogeny and a codon sequence alignment based on model assumptions, but they are prone to false positives due to alignment errors and can lack power. These problems are particularly pronounced when faced with high levels of indels and divergence. Leveraging the feature-detection capabilities of convolutional neural networks (CNNs), we achieve higher accuracy in detecting selection across a specific range of phylogenetic scenarios and evolutionary modes. This advantage is particularly evident with noisy data prone to misalignments. Our method shows some ability to account for these errors, where most statistical frameworks fail to do so in a tractable manner. We explore generalisability and identify future avenues to achieve broader utility. Once trained, our CNN model is faster at test time, making it a scalable alternative to traditional statistical methods for large-scale, multi-gene analyses. In addition to binary classification (inference of the presence or absence of positive selection during the evolution of the sequences), we use saliency maps to understand what the model learns and observe how this could be leveraged for sitewise inference of positive selection.

evolutionary biology↗

bioRxiv2024

The GPI sidechain of Toxoplasma gondii prevents parasite pathogenesis

Glycosylphosphatidylinositols (GPIs) are highly conserved anchors for eukaryotic cell surface proteins. The apicomplexan parasite, Toxoplasma gondii, is a widespread intracellular parasite of warm-blooded animals whose plasma membrane is covered with GPI-anchored proteins, and free GPIs called GIPLs. While the glycan portion is conserved, species differ in sidechains added to the triple mannose core. The functional significance of the Glc1,4GalNAc{beta}1-sidechain reported in Toxoplasma gondii has remained largely unknown without an understanding of its biosynthesis. Here we identify and disrupt two glycosyltransferase genes and confirm their respective roles by serology and mass spectrometry. Parasites lacking the sidechain on account of deletion of the first glycosyltransferase, PIGJ, exhibit increased virulence during primary and secondary infections, suggesting it is an important pathogenesis factor. Cytokine responses, antibody recognition of GPI-anchored SAGs, and complement binding to PIGJ mutants are intact. In contrast, the scavenger receptor CD36 shows enhanced binding to PIGJ mutants, potentially explaining a subtle tropism for macrophages detected early in infection. Galectin-3, which bind GIPLs, exhibits a slight enhancement of binding to PIGJ mutants, and the protection of galectin-3 knockout mice from lethality suggests that{Delta} pigj parasite virulence in this context is sidechain dependent. Parasite numbers are not affected by{Delta} pigj early in the infection in wildtype mice, suggesting a breakdown of tolerance. However, increased tissue cysts in the brains of mice infected with{Delta} pigj parasites indicate an advantage over wildtype strains. Thus, the GPI sidechain of T. gondii plays a crucial and diverse role in regulating disease outcome in the infected host. SummaryThe functional significance of sidechain modifications to the GPI anchor is yet to be determined because the glycosyltransferases responsible for these modifications have not been identified. Here we present identification and characterization of both T. gondii GPI sidechain-modifying glycosyltransferases. Removal of the glycosyltransferase that adds the first GalNAc to the sidechain results in parasites without a sidechain on the GPI, and increased parasite virulence. Loss of the second glycosyltransferase results in a sidechain with GalNAc alone, and no glucose added, and has negligible effect on parasite virulence. This indicates GPI sidechains as fundamental to host-parasite interactions.

microbiology↗

bioRxiv2024

Behaviour-based movement cut-off points in 3-year old children comparing wrist- with hip-worn actigraphs MW8 and GT3X

IntroductionBehaviour-based physical intensities have not undergone rigorous calibration in long-term recordings of 3-year-old childrens sleep/activity patterns. This study aimed at (i) calibrating activity counts of motor behaviour measured simultaneously with MotionWatch 8 (MW8) and ActiGraph (GT3X) in 3-year-old children, (ii) documenting movement intensities in 30s-epochs at wrist/hip positions, and (iii) evaluating the accuracy of cut-off agreements between different behavioural activities. MethodsThirty 3-year-old children of the NorthPop cohort performed six directed behavioural activities individually, each for 8-10 minutes while wearing two pairs of devices at hip and wrist position. Directly observed naturally-occurring behaviours included: watching cartoons, recumbent story listening, sit and handcraft, floor play with toys, engaging in a walk and a sprinting game. Receiver-Operating-Curve classification was applied to determine activity count thresholds and to assign context-guided, physical activity composite classes. ResultsActivity counts of MW8 and GT3X pairs of wrist-worn (r = 0.94) and hip-worn (r = 0.79) devices correlated significantly (p < 0.001). Activity counts at hip position were significantly lower compared to those at the wrist position (p < 0.001), irrespective of device type. Sprinting, floorball/walk and floorplay assigned as physically mobile classes achieved outstanding accuracy (AUC >0.9) and two sedentary and a motionless activities assigned into physically stationary classes achieved excellent accuracy (AUC >0.8). ConclusionThis study provides useful cut-offs for physical activity levels of preschool children using two different devices. Contextual information of behaviour is advantageous over intensity classifications only, because interventions reallocate time among behaviours, which allows to establish dose-response relationships between behavioural changes and health outcomes. Our comparative calibration is one step forward to inform behaviour-based public health guidelines for 3-year-old children.

neuroscience↗

bioRxiv2023

Extreme genome scrambling in cryptic Oikopleura dioica species

Genes are not randomly distributed throughout chromosomes. How gene order evolves and how selective constraints act to preserve or vary gene order, both at the macrosyntenic level of whole chromosomes or microsyntenic level of gene blocks, are central questions of evolutionary biology and genomics that remain largely unsolved. Here, after sequencing several genomes of the appendicularian tunicate Oikopleura dioica from different locations around the globe, we show an unprecedented amount of genome scrambling in animals with no obvious morphological differences, consistent with cryptic speciation. Our assemblies suggest that all members of this clade possess a common 3-chromosome karyotype, and that different species largely preserve gene content, despite the presence of thousands of rearrangements in gene order. The movements of genes are largely restricted to chromosome arms and sex-specific regions, which appear to be the primary unit of macrosynteny conservation, and examples of these within-arm movements can be seen in the Hox and Fgf gene families. Our approach employing whole-genome alignments demonstrates that segments containing protein-coding elements tend to be preserved at the microsyntenic scale, consistent with strong purifying selection, with appreciably less preservation of non-coding elements. Unexpectedly, scrambling did not preserve operon structure across species, suggesting an absence of selective pressure to maintain operon structure. As well, genome scrambling does not occur uniformly across all chromosomes, as short chromosome arms possess shorter genes, smaller operons, more breakpoints, and elevated dN/dS values compared to long chromosome arms. Estimation of divergence times among the cryptic O. dioica lineages yielded an estimated breakpoint accumulation rate of 6 to 25 breakpoints per megabase per million years, which is an order of magnitude higher than the rates for other ascidian tunicates or Drosophila species. Therefore, O. dioica appears to be an attractive animal system to unravel the mechanisms that underlie gene order and synteny conservation, as well as exploring the limits of genome scrambling without an apparent impact on phenotypic evolution.

genomics↗

bioRxiv2020

Telomere-to-telomere assembly of the genome of an individual Oikopleura dioica from Okinawa using Nanopore-based sequencing

BackgroundThe larvacean Oikopleura dioica is an abundant tunicate plankton with the smallest (65-70 Mbp) non-parasitic, non-extremophile animal genome identified to date. Currently, there are two genomes available for the Bergen (OdB3) and Osaka (OSKA2016) O. dioica laboratory strains. Both assemblies have full genome coverage and high sequence accuracy. However, a chromosome-scale assembly has not yet been achieved. ResultsHere, we present a chromosome-scale genome assembly (OKI2018_I69) of the Okinawan O. dioica produced using long-read Nanopore and short-read Illumina sequencing data from a single male, combined with Hi-C chromosomal conformation capture data for scaffolding. The OKI2018_I69 assembly has a total length of 64.3 Mbp distributed among 19 scaffolds. 99% of the assembly is in five megabase-scale scaffolds. We found telomeres on both ends of the two largest scaffolds, which represent assemblies of two fully contiguous autosomal chromosomes. Each of the other three large scaffolds have telomeres at one end only and we propose that they correspond to sex chromosomes split into a pseudo-autosomal region and X-specific or Y-specific regions. Indeed, these five scaffolds mostly correspond to equivalent linkage groups of OdB3, suggesting overall agreement in chromosomal organization between the two populations. At a more detailed level, the OKI2018_I69 assembly possesses similar genomic features in gene content and repetitive elements reported for OdB3. The Hi-C map suggests few reciprocal interactions between chromosome arms. At the sequence level, multiple genomic features such as GC content and repetitive elements are distributed differently along the short and long arms of the same chromosome. ConclusionsWe show that a hybrid approach of integrating multiple sequencing technologies with chromosome conformation information results in an accurate de novo chromosome-scale assembly of O. dioicas highly polymorphic genome. This assembly will be a useful resource for genome-wide comparative studies between O. dioica and other species, as well as studies of chromosomal evolution in this lineage.

genomics↗

bioRxiv2019

The vagus nerve is necessary for the rapid and widespread neuronal activation in the brain following oral administration of psychoactive bacteria

There is accumulating evidence that certain gut microbes modulate brain chemistry and have antidepressant-like behavioural effects. However, it is unclear which brain regions respond to bacteria-derived signals or how signals are transmitted to distinct regions. We investigated the role of the vagus in mediating neuronal activation following oral treatment with Lactobacillus rhamnosus (JB-1). Male Balb/c mice were orally administered a single dose of saline or a live or heat-killed preparation of a physiologically active bacterial strain, Lactobacillus rhamnosus (JB-1). 165 minutes later, c-Fos immunoreactivity in the brain was mapped, and mesenteric vagal afferent fibre firing was recorded. Mice also underwent sub-diaphragmatic vagotomy to investigate whether severing the vagus prevented JB-1-induced c-Fos expression. Finally, we examined the {Delta}FosB response following acute versus chronic bacterial treatment. While a single exposure to live and heat-killed bacteria altered vagal activity, only live treatment induced rapid neural activation in widespread but distinct brain regions, as assessed by c-Fos expression. Sub-diaphragmatic vagotomy abolished c-Fos immunoreactivity in most, but not all, previously responsive regions. Chronic, but not acute treatment induced a distinct pattern of {Delta}FosB expression, including in previously unresponsive brain regions. These data identify that specific brain regions respond rapidly to gut microbes via vagal-dependent and independent pathways, but suggest long-term exposure is required for the chronic brain activity associated with behavioural changes.

neuroscience↗

bioRxiv2018

Integrated Genomic Analysis of Hypoxia Genes across Cancer Types Identifies Significant Associations with Cancer Hallmarks

Hypoxia is a generic micro-environmental factor in most solid tumours. While most published literature focused on in vitro or single tumour type investigations, we carried out the first multi-omics pan cancer analysis of hypoxia with the aim of gaining a comprehensive understanding of its implication in tumour biology. A core set of 52 mRNAs were curated based on experimentally validated hypoxia gene sets from multiple cancer types. The 52 mRNAs collectively stratified high- and low-hypoxia tumours from The Cancer Genome Atlas (TCGA) database (9698 primary tumours) in each of the 32 cancer types available. High- hypoxia tumours had high expression of not only mRNA but also protein and microRNA markers of hypoxia. In a pan cancer transcriptomic analysis, [≥]70% of the known cancer hallmark pathways were enriched in high-hypoxia tumours, most notably epithelial mesenchymal transition potential, proliferation (G2M checkpoint, E2F targets, MYC targets) and immunology response. In a multi-omics analysis, gene expression-determined high- hypoxia tumours had a higher non-silent mutation rate, DNA damage repair deficiency and leukocyte infiltration. The associations largely remained significant after correcting for confounding factors, showing a profound impact of hypoxia in tumour evolution across cancer types. High-hypoxia tumours determined using the core gene set had a poor prognosis in 16/32 cancer types, with statistical significances remaining in five after adjusting for tumour stage and omics biomarkers. In summary, this first comprehensive in vivo map of hypoxia in cancers highlights the importance of this micro-environmental factor in driving tumour progression.

cancer biology↗

bioRxiv2017

sigQC: A procedural approach for standardising the evaluation of gene signatures

With the increase in next generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools, poised to make a large impact on the diagnosis, management and prognosis for a number of diseases. Increasingly, it is becoming necessary to determine whether a gene expression signature may apply to a dataset, but no standard quality control methodology exists. In this work, we introduce the first protocol, implemented in an R package sigQC, enabling a streamlined methodological and standardised approach for the quality control validation of gene signatures on independent data sets. The emphasis in this work is in showing the critical quality control steps involved in the generation of a clinically and biologically useful, transportable gene signature, including ensuring sufficient expression, variability, and autocorrelation of a signature. We demonstrate the application of the protocol in this work, showing how the outputs created from sigQC may be used for the evaluation of gene signatures on large-scale gene expression data in cancer.

bioinformatics↗