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PubMed2026

Functional unknomics of the SAR11 clade reveal hidden genetic potential underlying adaptation to bottom-up and top-down pressures.

UNLABELLED: A substantial fraction of the genes in bacteria lack detectable sequence similarity to genes with known functions. These functionally uncharacterized genes-collectively referred to as the "unknome"-represent a largely unexplored genetic repertoire harboring insights into marine bacterial ecology. In this study, we explored the function of the unknome of the SAR11 clade, the most abundant bacterial lineage in the ocean, with a particular focus on genes that provide insight into its ecology. Based on the Clusters of Orthologous Genes and Kyoto Encyclopedia of Genes and Genomes classifications, approximately 56% of SAR11 ortholog groups were classified as members of the unknome. Among the SAR11 unknome, we successfully inferred the functions of 57 ortholog groups that are conserved in the SAR11 clade by protein structure similarity searches and genomic context analyses. These ortholog groups include putative transporter components, supporting the current ecological understanding that the SAR11 clade is specialized in substrate uptake to adapt to oligotrophic marine environments. Furthermore, structural analysis indicated that the DUF2237-containing protein, enriched in marine environments, may interact with purine nucleotide-containing compounds. This may suggest the existence of unique nucleotide utilization mechanisms in marine bacteria. In addition, we identified candidate viral defense systems within the unknome, indicating that diverse defense systems are present in at least one-third of cultured SAR11 strains. The presence of these defense systems, even within streamlined SAR11 genomes, suggests that they confer significant ecological advantages. Our analyses provide insights into the genetic basis of bottom-up processes (adaptation to oligotrophic environments) and top-down processes (antiviral defense strategy) contributing to ecological success. IMPORTANCE: Many microbial genes have no experimentally established function, limiting our ability to explain how microorganisms adapt to their environments. We examined this uncharacterized gene space, or "unknome" in SAR11, the most abundant bacterial clade in the ocean, by integrating evolutionary conservation, genomic context, predicted protein structure, and environmental distribution. This approach enabled us to prioritize components of the SAR11 unknome, including a core unknome conserved across the clade and genes enriched in specific lineages, and to identify several candidates with possible ecological roles in nutrient acquisition and defense against viruses. Our results suggest that the SAR11 unknome contains important clues to the ecological success of SAR11 rather than merely reflecting incomplete annotation or gene-prediction artifacts. Our study highlights the potential value of unknome analysis for identifying ecologically relevant genes in environmental microorganisms.

Pelagibacterales↗

PubMed2026

Isolation, genomic characterization, and safety assessment of an O-desmethylangolensin-producing Clostridium beijerinckii strain from Chinese Stinky Tofu.

The health benefits of dietary soy isoflavones are largely mediated by specific microbial metabolites, such as O-desmethylangolensin (O-DMA). However, the diversity and application potential of O-DMA-producing strains remain poorly explored, primarily due to the limited availability of isolated strains, narrow ecological sources, and a lack of practical applications. In this study, an O-DMA-producing bacterium, designated strain FRJF5, was isolated from Chinese stinky tofu under anaerobic conditions and was identified as Clostridium beijerinckii. The biosynthesized O-DMA exhibited an enantiomeric excess (e.e.) of 78.6%. Based on phylogenetic and average nucleotide identity analyses against 235 public C. beijerinckii genomes, the clustering of FRJF5 with strains from diverse habitats-including industrial fermentation settings, animal feces, and soil-highlights the broad ecological diversity within this species. Functional gene mining and intra-species comparative genomics revealed a unique flavonoid metabolism gene cluster in FRJF5. Using apigenin as a representative flavonoid, we confirmed the successful conversion to 3-(4-hydroxyphenyl)-propionic acid. Moreover, the strain was predicted and verified to possess a substantial butyrate-producing capacity. Genomic screening for virulence or antibiotic resistance genes, combined with phenotypic tests (hemolysis, antibiotic susceptibility, and mouse gavage), revealed a favorable safety profile for strain FRJF5. Finally, intervention experiments in a mouse model of colitis supported its potential in alleviating the disease. Collectively, this study identifies C. beijerinckii FRJF5 as a strain capable of simultaneously producing O-DMA and butyrate, highlighting its potential for future applications in functional foods.IMPORTANCESoy isoflavones require gut bacterial conversion into bioactive metabolites-such as the anti-inflammatory compound O-desmethylangolensin (O-DMA)-to exert health benefits. Yet O-DMA-producing strains remain scarce, largely confined to fecal sources, and poorly characterized. Here, we isolated Clostridium beijerinckii FRJF5 from Chinese stinky tofu, an unexplored ecological niche. This strain not only produces enantiomerically enriched O-DMA but also co-produces butyrate, a metabolite known to strengthen gut barrier function. Genomic mining uncovered a unique flavonoid metabolism gene cluster responsible for this dual activity. Combined with favorable safety profiles, FRJF5 emerges as a strong candidate for functional food applications. This work expands the known diversity of O-DMA producers and bridges traditional fermented foods with next-generation probiotic development.

O-desmethylangolensin↗

PubMed2026

Genome-informed qPCR tracking revealed preferential persistence of Bacillus subtilis BS9 in the broiler chicken gastrointestinal tract.

This study aimed to develop a strain-specific quantitative PCR (qPCR) assay for Bacillus subtilis BS9 and characterize its persistence and spatial distribution in the broiler chicken gastrointestinal tract. Whole-genome sequencing and comparative genomic analysis identified a unique 110-bp sequence within a strain-specific genomic island, which was used to design a highly specific qPCR assay with excellent efficiency and sensitivity. In a 14-day in vivo trial, broiler chicks receiving daily oral doses of BS9 were analyzed using both culture-based methods and the newly developed qPCR. The assay was applied qualitatively, presence or absence, to detect BS9 in intestinal samples. BS9 was detected exclusively in the duodenum, jejunum, and cecum, with no presence in the gizzard or ileum. These findings demonstrate that BS9 exhibits region-specific persistence in the gut, likely reflecting adaptation to distinct physiological niches, which may contribute to its probiotic mechanisms.IMPORTANCEThis work provides the first detailed account of B. subtilis BS9's spatial persistence in poultry, revealing preferential adherence to specific intestinal regions. The strain-specific qPCR assay developed here offers a precise, culture-independent tool for tracking BS9 in complex gut environments. These insights into the genetic basis and tissue tropism of BS9 persistence advance our understanding of probiotic-host interactions and establish a framework for characterizing novel probiotic strains.

Bacillus subtilis↗

PubMed2026

Population heterogeneity in Helicobacter pylori PMSS1 shapes variable mouse infectivity: derivation of the homogeneous reference strain PMSS2.

UNLABELLED: Experimental infection models are widely used to investigate host-microbe interactions, often under the assumption that bacterial populations are genetically uniform. Here, we examined population heterogeneity in the widely used Helicobacter pylori strain PMSS1 and its relationship to variation in mouse infectivity. Single-colony isolates derived from PMSS1 displayed substantial differences in colonization efficiency, indicating that pre-existing variation within the population contributes to infection outcomes. To distinguish the effects of initial population heterogeneity from changes arising during infection, we analyzed PMSS2, a genetically homogeneous reference strain derived from PMSS1 that exhibited consistent infection phenotypes across independently isolated clones. Comparative genomic analysis of isolates recovered from infected mice revealed differences in the extent and patterns of genomic variation between PMSS1- and PMSS2-derived populations. These results demonstrate that variability in infection outcomes can arise from pre-existing heterogeneity within bacterial populations and highlight the importance of considering population composition when interpreting experimental infection studies. IMPORTANCE: Animal infection models are widely used to study how bacterial pathogens cause disease and change during infection. These studies often assume that the bacteria used for infection are genetically uniform. Our study shows that this assumption may not always hold. We found that a commonly used Helicobacter pylori strain contains hidden genetic diversity that leads to large differences in how well bacteria infect mice. By comparing this strain with a genetically uniform derivative, we show how differences present before infection can shape infection outcomes and influence the genetic changes observed during infection. Our findings highlight the importance of considering starting population diversity when interpreting experimental infection studies and are broadly relevant to research on microbial pathogenesis.

Helicobacter pylori↗

PubMed2026

Recurrent reversible mutations at gaf1 driving metastable TORC1 inhibitor resistance in fission yeast.

Metastable phenotypic inheritance is often attributed to epigenetic mechanisms, but reversible genetic alterations can produce similar instability. Here, we investigated the basis of unstable resistance to TORC1 inhibitor (rapamycin plus caffeine) in Schizosaccharomyces pombe. Six independent, metastable resistant mutants were isolated. Genetic mapping positioned the causal lesion to a single Mendelian locus, which sequencing identified as gaf1, encoding a GATA transcription factor and a key negative regulator of growth downstream of TORC1. In each mutant, distinct loss-of-function mutations (insertions, deletions, or point mutations) were found in gaf1 in the resistant state, and these mutations precisely reverted to the wild-type sequence upon loss of resistance. Restoring the wild-type gaf1 allele abolished resistance, indicating that reversible genetic disruption of gaf1 is both necessary and sufficient for the metastable phenotype. Furthermore, strong resistance in several strains from a genome-wide deletion library was due to secondary, inactivating mutations in gaf1, underscoring its role as a recurrent adaptive target under rapamycin plus caffeine treatment. Mechanistically, gaf1 inactivation established a distinct basal transcriptome and pronounced derepression of translation and metabolic programs upon drug treatment. While rapamycin plus caffeine triggered extensive chromatin remodeling and H3K9 methylation contributed partially to resistance, these epigenetic changes were most consistent with a downstream modifying layer. Our study shows that metastable drug resistance in fission yeast is predominantly associated with recurrent, reversible genetic inactivation of the central transcriptional regulator gaf1, demonstrating how rapidly reversible genetic switches can drive adaptive evolution.IMPORTANCEDistinguishing between genetic and epigenetic inheritance is fundamental to understanding how cells adapt to environmental stress. In the fission yeast Schizosaccharomyces pombe, rapid and reversible drug resistance is often assumed to be driven by epigenetic switches that change gene activity without altering DNA. However, our study reveals that this instability can be caused by physical mutations in a single gene, gaf1, which acts as a genetic toggle. These mutations appear under drug pressure and precisely revert to the original sequence when the drug is removed. We also demonstrate that these spontaneous mutations can contaminate standard laboratory yeast collections, leading to potential misinterpretation of experimental data. These findings broaden our understanding of unstable inheritance and show that DNA sequences can be far more dynamic than previously recognized during rapid evolution and the development of drug resistance.

TORC1 signaling↗

PubMed2026

Emerging food- and waterborne pathogen Arcobacter in wastewater: diversity and antibiotic resistance.

Arcobacter spp. are emerging food- and waterborne pathogens frequently detected in wastewater. Despite their high abundance in wastewater, Arcobacter diversity, antibiotic resistance, and genomic traits remain poorly characterized. To address these knowledge gaps, we conducted a comprehensive study of Arcobacter spp. in influent, effluent, and activated sludge from a Finnish wastewater treatment plant using full-length 16S rRNA gene sequencing, isolate-based genomics, and phenotypic antibiotic susceptibility testing. Arcobacter spp. were highly abundant in raw sewage but substantially removed during treatment. Four Arcobacter species were identified, dominated by Arcobacter cryaerophilus and Arcobacter suis. A proportion of amplicon sequence variants unclassified to species-level revealed potentially unexplored Arcobacter diversity. For the first time, we observed intragenomic variability in 16S rRNA gene copies of A. cryaerophilus, highlighting the importance of integrating culture-based and culture-independent approaches. Phenotypic testing revealed high proportions of non-wild-type isolates for clinically relevant antibiotics, including ampicillin, cefotaxime, tetracycline, and erythromycin. Genomic analyses showed that antibiotic resistance profiles were primarily mediated by chromosomally encoded determinants, including β-lactamases, efflux systems, and point mutations. Additionally, a broad arsenal of chromosomal and plasmid-borne resistance genes to heavy metals, biocides, and organic solvents was detected, reflecting adaptations to the wastewater environment. These findings provide novel insights into Arcobacter species-level diversity, resistance mechanisms, and ecological adaptations in anthropogenically influenced environments. The study highlights the significance of Arcobacter for public health and establishes a foundation for further research.IMPORTANCEArcobacter spp. are emerging human and animal pathogens that exhibit increasing resistance to clinically relevant antibiotics. Most community-acquired infections are linked to exposure through contaminated food and water, yet studies investigating their occurrence and diversity in wastewater remain scarce. Here, we focus on wastewater as an abundant source of Arcobacter spp. and a potential dissemination route contributing to downstream contamination of surface waters, irrigated soils, and possibly the food chain. By characterizing the species-level diversity, genomic traits, and antibiotic resistance profiles of Arcobacter spp. in wastewater, this study provides critical insights into the ecology and epidemiology of this ubiquitous genus.

Arcobacter↗

PubMed2026

Comparative genomics of the monophasic variant of Salmonella Typhimurium: analysis of Colombian genomes and their relationship with international lineages.

The monophasic variant of Salmonella enterica serovar Typhimurium (STVM) represents a growing threat to global public health owing to its wide dissemination, capacity to adapt to multiple hosts, and antimicrobial resistance. In this study, 98 STVM isolates recovered in Colombia (57 from humans and 41 from pig farms and abattoirs) were genomically characterized between 2015 and 2022 and compared with 102 representative genomes of international lineages by whole-genome sequencing (WGS) and phylogenomic analysis. Phylogenomic analysis revealed the existence of two well-defined endemic lineages in Colombia (Clusters 1 and 2), arising from independent introduction events and subsequent local stabilization. Both lineages comprise isolates of human and swine origin without clear phylogenetic separation by host species, suggesting active zoonotic cocirculation and closely integrated interspecies transmission dynamics. Marked differences were observed in the accessory genome, including the differential presence of prophages (e.g., Gifsy-2, Fels-2, SW9), virulence plasmids, and resistance profiles. The Colombian lineages exhibited a high frequency of the pSTV plasmid (85%, n = 84/98) and a substantial burden of resistance determinants to quinolones (such as qnrB19, 74.5%; gyrA S83F mutation, 19.4%), phenicols (floR), tetracyclines (tetA, tetB), β-lactams (blaTEM-1B), and heavy metals. In contrast, the Colombian genomes clustered with the European ST34 lineage lacked pSTV but retained resistance and heavy metal operons. These findings demonstrate that international and endemic lineages coexist in Colombia with independent evolutionary trajectories, underscoring the need to strengthen genomic surveillance under the "One Health" approach to anticipate emerging threats and develop integrated control strategies.IMPORTANCEThe monophasic variant of Salmonella Typhimurium (STVM) has emerged as a predominant serovar in both humans and swine internationally. In Colombia, a fundamental question driving this study was whether local isolates belonged to international lineages or represented endemic strains. This study provides the first comprehensive genomic characterization demonstrating that two Colombian endemic lineages circulate simultaneously between humans and pigs without phylogenetic separation by host species, confirming active zoonotic transmission. The results demonstrate the coexistence of both lineages, each with distinctive repertoires of mobile genetic elements and specific antimicrobial resistance profiles. Understanding these transmission dynamics and evolutionary patterns is crucial for public health, as it demonstrates how zoonotic pathogens can establish locally adapted lineages with distinct resistance patterns. The genomic evidence of sustained interspecies circulation highlights the critical need for integrated surveillance strategies under the "One Health" framework. This will enable anticipating emerging threats, tracing transmission routes, and developing targeted interventions in food production systems.

One Health↗

PubMed2026

Incidence patterns and genetic validation of primary glaucoma subtypes among 1 million adults in China and the UK.

BACKGROUND/AIMS: Primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) are distinct diseases, yet many glaucoma cases in population-based datasets lack subtype specification. We assessed incidence patterns of glaucoma subtypes in China and the UK and used genetic evidence to infer the likely subtype composition of cases recorded as unspecified glaucoma. METHODS: Incident primary glaucoma was identified from linked inpatient records in the prospective China Kadoorie Biobank (CKB; n=512 504) and UK Biobank (UKB; n=492 329) studies. Cohort-specific phenotyping algorithms defined POAG, PACG and unspecified glaucoma. Adjusted incidence rates were estimated by direct standardisation. To support subtype inference, polygenic risk scores (PRSs) were constructed using ancestry-specific genome-wide association studies, including a new East Asian PACG meta-analysis, and tested for association with glaucoma phenotypes using multivariable logistic regression. RESULTS: Over 12 years of follow-up, 1658 primary glaucoma cases were identified in CKB and 7643 in UKB. Most (>68%) cases lacked subtype specification. Incidence increased with age and was twofold higher among women for PACG in both cohorts and for unspecified glaucoma in CKB. In UKB, POAG incidence was fivefold higher among Black than White participants, with a similar but attenuated pattern for unspecified glaucoma. PRS analyses indicated that unspecified glaucoma closely aligned with PACG in CKB but was more heterogeneous in UKB. CONCLUSION: Healthcare-recorded incidence patterns for POAG and PACG were consistent with established demographic risk factors, whereas unspecified glaucoma showed differences in subtype composition between populations. Integrating epidemiological and genetic evidence improves interpretation of glaucoma phenotypes when detailed clinical information is unavailable.

Epidemiology↗

PubMed2026

Genomic Screening for Infants and Reproductive Adults.

Recent progress in genomic sequencing, bioinformatics, cloud computation, and artificial intelligence is advancing a more mature understanding of the architecture of childhood genetic diseases. This knowledge and these technologies are enabling expanded genomic screening of infant and reproductive adult populations. With many new disease-modifying and curative therapies in development and approval processes, there exists unparalleled opportunity to identify, treat, and decrease the population burden of genetic disease and transform medical genetics. Broad implementation of genomic population screening, however, requires investments for overcoming remaining evidence gaps and operational challenges, and for delivery in a sustainable manner that is acceptable to parents, prospective parents, and physicians.

Journal Article↗

PubMed2026

The Pathogenesis of Epithelial Ovarian Cancer.

Epithelial ovarian cancer is not a single disease but a group of biologically distinct malignancies that include serous (high-grade and low-grade), endometrioid, clear cell, and mucinous carcinomas, along with other rare subtypes. Integrating clinicopathological analyses, genomic and multiomic data, and experimental investigations in model systems has revealed the pathogenesis of the various histologic subtypes. A unique feature of epithelial ovarian cancer is that most of these tumors are now recognized to arise not from ovarian tissue but from the fallopian tube or endometrium, the latter in the context of ovarian endometriosis. Studies of precursor lesions have revealed complex evolutionary trajectories and the earliest molecular events in their development. Recent single-cell and spatial technologies further elucidate the roles of intratumoral heterogeneity and the tumor microenvironment in disease progression. This review summarizes these advances from the perspective of tissue of origin and highlights their implications for prevention, early detection, and therapeutic development.

Journal Article↗

PubMed2026

Fault Lines in the Genome: Somatic DNA Mutations in Aging and Neurodegeneration.

The human genome is both fragile and resilient: prone to alteration yet protected by extensive repair mechanisms. With age, individuals accumulate genetic damage from environmental factors and cell-intrinsic processes, with effects ranging from benign nucleotide shifts to disease-driving mutations. Such alterations to the genetic code outside the germline are described as somatic mutations and display striking heterogeneity across cell types. Recently, somatic mutations have emerged as a hallmark feature of aging in the body's longest-lived tissue: the central nervous system (CNS). The distinctively long lifespan, high metabolism, electrochemical activity, and unique epigenome of CNS cells may render them especially vulnerable to mutational accumulation. The CNS therefore provides a model for understanding how somatic mutations drive cellular dysfunction beyond an established role in cancer. Here, we review the somatic mutations that arise in the brain across lifespan, the mechanisms that lead to their formation, and their potential contributions to aging and age-related disease.

Journal Article↗

PubMed2026

Identification of a necroptosis-related lncRNA prognostic signature and the hub RBP HNRNPK in esophageal squamous cell carcinoma.

ObjectiveEsophageal squamous cell carcinoma (ESCC) is a malignant tumor with poor prognosis. Necroptosis is important for tumor immunity, but its role in ESCC remains unclear. This retrospective bioinformatics study aimed to investigate the prognostic value of necroptosis-related long non-coding RNAs (lncRNAs) and to identify key lncRNA-binding proteins (RBPs) in ESCC patients.MethodsRNA transcriptome and clinical data of ESCC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Necroptosis-related lncRNAs were identified through correlation analysis with necroptosis-related genes, subjected to consensus cluster analysis, and used to construct a prognostic risk model via least absolute shrinkage and selection operator (LASSO) regression. The hub RBP was experimentally validated by quantitative polymerase chain reaction (qPCR) using 30 pairs of ESCC and adjacent normal tissues from patients who underwent surgical resection.ResultsA total of 30 necroptosis-related lncRNAs were significantly correlated with overall survival (OS). The upregulated lncRNAs in the risk model were associated with high immune scores, innate immune cell infiltration, cluster 2 classification, and advanced T-stage disease (p < 0.05). Three hub RBPs (HNRNPA1, HNRNPC, and HNRNPK) were identified through protein-protein interaction network analysis. qPCR confirmed that HNRNPK was significantly overexpressed in ESCC tissues compared to adjacent normal tissues (p < 0.05).ConclusionsThe necroptosis-related lncRNA risk model is an independent prognostic factor for ESCC patients. HNRNPK was identified as a hub RBP significantly overexpressed in ESCC tissues. We hypothesize that HNRNPK may promote tumor progression through regulating proto-oncogene expression or modulating the immune microenvironment, though this requires further mechanistic validation.

Humans↗

PubMed2026

Prognostic value and immune landscape implications of using a novel homologous recombination repair pathway signature in prostate cancer: A retrospective cohort study.

ObjectiveAlthough the homologous recombination repair (HRR) pathway plays a critical role in the treatment of prostate cancer, its prognostic value remains incompletely understood. This study aimed to identify HRR pathway-related biomarkers with clinical utility for prognosis prediction and treatment guidance.MethodsWe analyzed genomic data from The Cancer Genome Atlas and Chinese patients with prostate cancer in a retrospective cohort study using a comprehensive multiomics approach to characterize a novel HRR-related prognostic signature and its immune implications.ResultsIn the Chinese cohort, 25.6% of the patients exhibited homologous recombination deficiency scores >42, whereas 27.3% carried ≥1 HRR gene mutation. We established a prognostic HRR signature (homologous recombination deficiency score >32, HRR gene mutations, and Signature 3) associated with poor outcomes. Compared with The Cancer Genome Atlas data, the Chinese cohort demonstrated a higher prevalence of HRR signature. Patients with HRR signatures demonstrated significantly increased genomic instability markers, including segment number, alteration burden, aneuploidy score, and intratumor heterogeneity. The HRR signature was associated with higher neoantigen load but reduced T cell receptor (TCR) evenness. Immunologically, HRR-positive tumors were associated with computationally inferred immune profiles suggestive of reduced immune activity, characterized by depletion of T-helper 17 cell; downregulation of TLR4/PDCD1LG2 expression; and upregulation of ARG1, IFNG, KIR2DL3, and CXCL9. However, these findings are descriptive and require experimental validation.ConclusionOur findings identify a clinically relevant HRR signature that warrants investigation as a potential predictive biomarker for prostate cancer prognosis and treatment response. This biomarker provides new insights for personalized therapy and may help optimize patient outcomes.

Humans↗

PubMed2026

Genetic Variants of NRAMP1 and Hepcidin (HAMP) in Cancer Patients Infected with Human Herpesvirus-6.

Human herpesvirus-6 (HHV-6) is involved in immune modulation and contributes to cancer development through interactions with host genetic factors. Hepcidin (HAMP) and NRAMP1 genes play essential roles in iron metabolism and innate immunity, yet their polymorphisms remain poorly investigated in HHV-6-associated cancers. This study investigated the association between HAMP and NRAMP1 gene polymorphisms and HHV-6 infection in 40 confirmed HHV-6-positive cancer patients compared with 40 non-cancer, HHV-6-negative controls. Genomic DNA was extracted and verified by agarose gel electrophoresis. Hepcidin polymorphisms were analyzed using Tetra-ARMS PCR, while NRAMP1 (3'UTR) polymorphism was detected by PCR-RFLP. Cancer patients exhibited wild-type, mutant, and heterozygous hepcidin genotypes, whereas controls predominantly showed the wild-type genotype. Although allele frequency analysis revealed no statistically significant difference for the G and TG+ alleles between groups (p = 0.23), the hepcidin A allele (521 bp) was more frequent among cancer patients, suggesting a possible association with increased cancer susceptibility (odds ratio = 2.111). For NRAMP1, three genotypic patterns were identified (TG-/TG-, TG+/TG+, and TG-/TG+), and while no significant between-group difference was detected (p = 0.23), the TG+ allele demonstrated a potential two-fold increased cancer risk among carriers. These findings suggest that specific allelic variants-particularly the hepcidin A allele and NRAMP1 TG+ allele-may contribute to cancer susceptibility in HHV-6-infected individuals, highlighting a possible genetic-viral interaction that influences immune and iron-regulatory pathways in cancer development.

HHV-6↗

PubMed2026

PKMYT1 is a targetable vulnerability in del(17p) high-risk multiple myeloma.

Deletion of chromosome 17p [del(17p)] is among the most adverse cytogenetic abnormalities in multiple myeloma (MM). By integrating RNA sequencing data from cells of patients with MM with genetic dependency data from MM cell lines, we identified protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the WEE family, as a potential therapeutic target in MM cells harboring del(17p). Genetic suppression or pharmacological inhibition of PKMYT1 activity with the selective inhibitor RP-6306 triggered accumulation of DNA damage, micronucleus formation, and mitotic catastrophe, resulting in preferential cell death in del(17p) MM cells while largely sparing del(17p)- MM cells and healthy cells. RP-6306 also reduced tumor burden and extended survival in vivo in both xenograft and TP53-deficient syngeneic models. Collectively, our findings nominate PKMYT1 as an actionable target and support PKMYT1 inhibition as a biomarker-driven therapeutic strategy for patients with del(17p) or TP53-deficient MM.

Humans↗

PubMed2026

The N6-methyladenosine reader IGF2BP2 in T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous and aggressive lymphoid neoplasm that lacks pathogenic biomarkers of RNA modification with therapeutic potential. IGF2BP2 is recognized as an N6-methyladenosine reader critically involved in oncogenesis. In this study, we observed consistently high expression of IGF2BP2 across common nodal PTCL subtypes in 3 independent external cohorts, which was further confirmed in our RNA-sequencing (RNA-seq) data set of 196 patients with newly diagnosed PTCL. Both in vitro and in vivo, IGF2BP2 promoted tumor cell growth and inhibited CD8+ T-cell infiltration within the tumor microenvironment. Mechanistically, IGF2BP2 bound to endosome-related genes (RAB4, VPS35, RAB9, and STAM) to maintain their stability, which resulted in enhanced endocytic activity and increased internalization of membrane proteins, and ultimately induced tumor cell proliferation and inhibition of CD8+ T-cell-mediated tumor cytotoxicity. The relationship between IGF2BP2 and endocytosis-associated genes was confirmed using RNA-seq data from patients with PTCL. IGF2BP2 as an upstream regulator of both tumor growth and immune suppression was further demonstrated in patient-derived xenograft models and a coculture system established using tumor samples from patients with PTCL and peripheral blood mononuclear cells. Notably, therapeutic targeting of IGF2BP2 with CWI1-2 suppressed endocytosis and impeded tumor growth in both cell lines and patient-derived xenograft models. Collectively, our findings highlight IGF2BP2 as a clinically relevant oncogenic driver in PTCL that integrates tumor-intrinsic growth signals with immune evasion through endocytosis-centered regulation, providing a novel therapeutic rationale for RNA modification-based strategies that concurrently target tumor cells and the tumor microenvironment.

Humans↗

PubMed2026

Transcriptome-based epigenetic screening identifies DNA hypermethylation signatures as prognostic biomarkers in oral squamous cell carcinoma.

Promoter DNA hypermethylation is a key epigenetic mechanism of gene silencing in cancer, yet the DNA hypermethylome of oral squamous cell carcinoma (OSCC) and its prognostic relevance remain poorly characterized. Here, we systematically identified and validated novel hypermethylated genes with prognostic significance in OSCC using a genome-wide discovery and multi-platform validation strategy. Candidate genes were first identified by pharmacologic demethylation combined with RNA sequencing across OSCC cell lines, then validated by quantitative RT-PCR, methylation-specific PCR, and bisulfite sequencing in OSCC cell lines, normal oral mucosa, and primary OSCC tumors, with independent confirmation in the TCGA-HNSC dataset. Immunohistochemistry confirmed protein-level silencing, and Kaplan-Meier survival analysis assessed prognostic significance across both cohorts. This pipeline identified five candidate genes, GPX3, ANG, CTGF, GPRC5B, and BAMBI, exhibiting cancer-specific promoter hypermethylation associated with transcriptional and protein silencing in OSCC. Validation in oral cavity tumor samples extracted from the TCGA-HNSC dataset confirmed tumor-specific hypermethylation and revealed significant inverse correlations between methylation and expression for GPX3, GPRC5B, and CTGF. Notably, CTGF hypermethylation was independently associated with poor overall survival in both cohorts (institutional cohort, p=0.03; oral tumor subset from TCGA-HNSC, p=0.01), and a combined ANG+CTGF methylation signature showed superior and reproducible prognostic performance across both platforms. Pathway analysis linked these genes to epithelial-mesenchymal transition and interferon response signaling. This study establishes the first validated DNA methylation biomarker panel for OSCC prognosis, identifying CTGF hypermethylation as a robust prognostic driver with translational potential for clinical risk stratification.

Humans↗

PubMed2026

Cross-Ancestry and Phenome-Wide Associations of Cancer-Specific Polygenic Risk Scores.

PURPOSE: Genome-wide association studies have identified many common variants associated at low effect sizes with various cancers. Summing the effects of these variants into polygenic risk scores (PRS) can improve cancer risk prediction. However, cross-cancer and cross-phenotype pleiotropic associations of cancer-specific PRS are limited. METHODS: Using logistic regression models, we tested the association of 13 cancer-specific PRS with curated phenotypes representing the same 13 cancers and 340 cancer and cardiometabolic phecodes in 560,287 individuals (114,255 African ancestry [AFR] and 446,032 European ancestry [EUR]) from the Million Veteran Program. Models were stratified by ancestry and used age, principal components, and cancer-specific PRS per standard deviation as independent variables, and correction was applied for multiple comparisons. RESULTS: All 13 cancer-specific PRS were significantly associated with their respective cancers among EUR individuals with odds ratios per standard deviation of PRS (odds ratio [OR]) 1.05-1.70. Among AFR individuals, the effect sizes of the cancer PRS were lower, with OR 1.01-1.48, and cancer-specific PRS were significantly associated with their respective cancers for five of 13 cancers (bladder, breast in female patients, colorectal, prostate, and thyroid). In cancer-cancer pleiotropy studies, only the renal cancer-specific PRS was significantly associated with skin cancer (OR = 1.04, P = 4.5 × 10-06) among EUR individuals. PheWAS demonstrated five positive pleotropic associations with cardiometabolic conditions (thyroid cancer PRS with thyroid goiter, oral cancer PRS with diabetes phenotypes, and hypothyroidism) and two negative associations (oral and lung cancer PRS separately with coronary artery disease). CONCLUSION: Cancer PRS have stronger associations per cancer among EUR versus AFR individuals. In contrast to PRS of other chronic diseases, the majority of cancer-related PRS are highly specific and pleiotropic associations with other cancers and cardiometabolic traits are uncommon.

Female↗