Biology subjects

Zhivagui, M.

Publications and source records attributed to Zhivagui, M..

6 recordsLinked to original sources

bioRxiv2026

A Compendium of 49 Experimental SBS Signatures for Decoding Human Cancer Mutational Processes

Human cancer genomes harbor distinct mutational patterns that reflect past processes of DNA damage and repair. However, the precise attribution of these signatures to specific chemical carcinogens lacks a standardized experimental reference framework. To address this gap, we curated 4,282 genome-wide sequencing datasets from 42 model systems across five species exposed to 146 cancer-risk agents. This platform yielded 49 robust experimental single-base substitution signatures (eSS), with 28 matching 19 established COSMIC signatures and 21 defining novel mutational processes. We reconstructed 24 COSMIC signatures, assigning candidate etiologies to five signatures of unknown origin and revising two contested assignments. Pan-cancer decomposition detected four eSS-like mutational processes enriched in smokers across 4,951 tumors. Lastly, independent single-molecule sequencing of primary human organoids reproduced these profiles with high fidelity, confirming true platform-independent biological reproducibility across complex human models. This eSS repertoire provides a reference that links human mutational processes to mechanistic classes of DNA damage.

genomics↗

bioRxiv2025

SigRescueR: A Pan-System Framework for Noise Correction and Mutational Signature Identification Across Sequencing Platforms

Mutational signatures serve as molecular fingerprints of the biological processes and exposures that shape cancer genomes. However, accurate signal recovery remains challenging due to pervasive background variants, sequencing artifacts, technical noise, and platform-specific biases that obscure true mutagenic patterns, hampering biomarker discovery and mechanistic interpretation. Here we introduce SigRescueR, a rigorous, pan-system, computational framework designed for noise correction and mutational signature identification. SigRescueR applies statistically robust baseline correction to effectively disentangle true mutational signals from confounding noise and artifacts. When applied to extensive datasets spanning experimental models and human cancers, SigRescueR reliably identified canonical mutational signatures associated with environmental mutagens such as colibactin, benzo[a]pyrene, and UV radiation, and chemotherapeutic agents, namely 5-fluorouracil and cisplatin. SigRescueR effectively operated across diverse mutation classes, including single base substitutions, insertions and deletions, and doublet base substitutions, while also integrating strand bias and duplex sequencing data for toxicology applications. SigRescueR offers a unified, high-precision platform that seamlessly integrates cancer genomics, molecular toxicology, and mechanistic studies. It enables precise mapping of mutagenic processes and identification of robust genomic biomarkers of environmental and therapeutic exposures, providing a transformative framework for translational cancer research. Availability and implementationSigRescueR is implemented in R and provided as open-source software on GitHub at https://github.com/ZhivaguiLab/SigRescueR/

genomics↗

bioRxiv2025

Multi-omics profiling reveals microenvironmental remodeling as a key driver of house dust mite-induced lung cancer progression

Chronic exposure to the common aeroallergen house dust mite (HDM) induces lung inflammation and DNA damage, but its impact on lung cancer development remains largely unexplored. Using whole-genome sequencing, RNA-seq, and DNA methylation profiling, we assessed HDM effects in lung epithelial cell lines and a mouse orthotopic lung cancer model. HDM accelerated tumor growth without altering mutational burden. Transcriptomic and epigenetic analyses revealed tissue-specific effects: in normal lung, HDM enhanced pro-inflammatory and immune activation programs, whereas in tumors it suppressed T cell responses, antigen presentation, and chemokine signaling. Immune deconvolution showed a shift toward myeloid enrichment and lymphoid suppression, with reduced cytotoxic T and NK signatures. Notably, HDM-driven tumor promotion was abolished in Il17a-/- but not Il1b-/-mice, identifying IL-17A as a critical mediator. These findings demonstrate that chronic aeroallergen exposure reshapes the lung microenvironment to promote immune suppression and accelerate lung cancer progression. HighlightsChronic house dust mite (HDM) exposure accelerates lung tumor growth through non-mutagenic, immune-mediated mechanisms. HDM activates pro-inflammatory and immune programs in normal lung tissue but suppresses antitumor T cell responses in tumors. Multi-omics profiling reveals epigenetic silencing of immune genes and a myeloid-enriched, lymphoid-deficient tumor microenvironment. HDM-driven tumor promotion depends on IL-17A but not IL-1{beta}, establishing IL-17A as a central driver of lung tumor promotion.

cancer biology↗

bioRxiv2025

A Universal Duplex Sequencing Approach for Accurate Detection of Somatic Mutations

Ultra-accurate detection of rare somatic mutations is critical for understanding mutational processes in human disease, aging, and environmental exposures, yet current methods are limited by error rates, restricted genome coverage, and high DNA input. We present UDSeq, a duplex sequencing protocol combining random fragmentation, efficient UMI ligation, and quantitative input control to achieve near-complete genome/exome representation from as little as 100 pg DNA. Benchmarking in human sperm estimates a UDSeq error rate of [~]2.5x10-9 per base pair. UDSeq captures mutational signatures from heterogeneous populations without clonal expansion, reproduces exposure-specific patterns in cell lines and rodent models, and enables cross-species profiling. Compared with prior duplex methods, UDSeq yields up to fourfold more usable duplex molecules, improves library conversion, and remains cost-effective. We include a step-by-step protocol with quality-control checkpoints for fragment size, ligation yield, library conversion, and duplication rate. UDSeq provides a scalable, low-input platform for accurate profiling of somatic mutagenesis.

genomics↗

bioRxiv2021

Pre-mutagenic and mutagenic changes imprinted on the genomes of mammalian cells after irradiation with a nail polish dryer

Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of mammalian cells. These results have far-reaching implications in regard to public health and to preventing skin cancer due to consumer-based exposure to ultraviolet light from artificial sources.

cancer biology↗

bioRxiv2018

Experimental analysis of exome-scale mutational signature of glycidamide, the reactive metabolite of acrylamide

Acrylamide, a probable human carcinogen, is ubiquitously present in the human environment, with sources including heated starchy foods, coffee and cigarette smoke. Humans are also exposed to acrylamide occupationally. Acrylamide is genotoxic, inducing gene mutations and chromosomal aberrations in various experimental settings. Covalent haemoglobin adducts were reported in acrylamide-exposed humans and DNA adducts in experimental systems. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic metabolite capable of inducing rodent tumors at various anatomical sites. In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and whole-exome sequencing analyses in an established exposure-clonal immortalization system based on mouse embryonic fibroblasts. Sequencing and computational analysis revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, followed by T:A>C:G and C:G>A:T mutations exhibiting specific trinucleotide contexts and significant transcription strand bias. Computational interrogation of human cancer genome sequencing data indicated that a combination of the glycidamide signature and an experimental benzo[a]pyrene signature are nearly equivalent to the COSMIC tobacco-smoking related signature 4 in lung adenocarcinomas and squamous cell carcinomas. We found a more variable relationship between the glycidamide- and benzo[a]pyrene-signatures and COSMIC signature 4 in liver cancer, indicating more complex exposures in the liver. Our study demonstrates that the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutation signature laboratory experimentation contributes to the elucidation of cancer causation.\n\nA 40-word summaryInnovative experimental approaches identify a novel mutational signature of glycidamide, a metabolite of the probable human carcinogen acrylamide. The results may elucidate the cancer risks associated with exposure to acrylamide, commonly found in tobacco smoke, thermally processed foods and beverages.

genomics↗