Biology subjects

Abedi-Ardekani, B.

Publications and source records attributed to Abedi-Ardekani, B..

5 recordsLinked to original sources

bioRxiv2026

Systemic mutagen exposures reported by normal kidney cell genomes

Lifestyle, environmental and other exposures to exogenous mutagens generate somatic mutations in normal human cells in vivo and increase cancer risk. However, the global repertoire of exogenous mutagen exposures is uncertain. The mutational signatures of mutagens in normal tissues offer opportunities to detect such exposures and survey them at population level. Using single-molecule duplex sequencing of normal kidney (n=319) and blood (n=272) samples from 10 countries, we show that normal kidney cell genomes report an extensive repertoire of somatic mutational signatures. Microdissection of kidney structures revealed that proximal tubules exhibit higher mutation rates than other components of the nephron and most normal cell types despite low cell division rates. This is explained by marked enrichment of mutational signatures due to known exogenous carcinogenic mutagens including the plant-derived aristolochic acids, as well as several signatures of unknown causes including an unknown agent prevalent in Japan (SBS12), and signatures of uncertain origins (SBS40b and SBS40c). The results suggest the existence of multiple, common, systemically circulating mutagens affecting human populations and indicate that the genomes of kidney proximal tubule cells report such exposures with high sensitivity.

genomics↗

bioRxiv2025

Genome-scale multi-organ analysis of mutagenic effects of ethanol and acetaldehyde in Sprague Dawley rats

Alcohol consumption is a major cancer risk factor, particularly for head and neck cancers, including the oral cavity. Acetaldehyde, the primary genotoxic metabolite of ethanol, may play key roles in oral carcinogenesis, though the mechanisms remain unclear. While mutational signatures SBS16, DBS4, and ID11 have been tentatively linked to alcohol use, they are not exclusive to alcohol-related cancers. In this study, we examined the genome-wide in vivo mutagenic effects of ethanol and acetaldehyde by analyzing tumors from the cheek, Zymbal gland, larynx, forestomach, and liver of rats chronically exposed to these compounds. Signature analysis revealed exposure-specific, early-onset formation of SBS17 in [~]28% of head and neck tumors, suggesting inflammation and/or oxidative damage as potential mediators of carcinogenesis. Cancer driver gene analysis identified a relative enrichment of exposed tumors with mutations in the Tp53 and Mtor genes. No notable exposure-specific changes were observed in doublet-base substitutions, indel signatures, or copy number variants. Notably, SBS16, DBS4, and ID11 were absent. Our findings suggest direct mutagenicity may not be the main driver of alcohol-related cancer. Other harmful cellular effects, undetectable by whole genome sequencing, may be involved. Our findings suggest that SBS17 could function as a potential exposure-specific molecular marker of alcohol-related cancers in humans.

cancer biology↗

bioRxiv2021

An international report on bacterial communities in esophageal squamous cell carcinoma

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One proposed biological pathway linking poor oral health and ESCC involves the alteration of the microbiome. Thus, we performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors and WGS of synchronous collections of saliva specimens from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella, and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed a similar tumor enrichment of the ESCC-associated bacterial community in these cancers. Because these genera are traditionally considered members of the oral microbiota, we explored if there is a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes are significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of ESCC patients. Longitudinal studies of the pre-diagnostic oral microbiome are needed to investigate whether these cross-sectional similarities reflect temporal associations.

microbiology↗

bioRxiv2019

Needlestack: an ultra-sensitive variant caller for multi-sample next generation sequencing data

The emergence of Next-Generation Sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analyzing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub plateform: https://github.com/IARCbioinfo/needlestack.

bioinformatics↗

bioRxiv2017

Genome-Scale Mutational Signatures Of Aflatoxin In Cells, Mice And Human Tumors

Aflatoxin B1 (AFB1) is a mutagen and IARC Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here we present the first whole genome data on the mutational signatures of AFB1 exposure from a total of > 40,000 mutations in four experimental systems: two different human cell lines, and in liver tumors in wild-type mice and in mice that carried a hepatitis B surface antigen transgene - this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly-sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.

cancer biology↗