Aug 2026· Epigenomes· Vol 10, pp. 56· 0 citations· 41 references
Medicine
TL;DR
This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis.
Abstract
Background/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare, highly aggressive form of pediatric myelodysplastic/myeloproliferative neoplasm characterized by molecular heterogeneity and constitutive activation of the RAS signaling pathway. This study aimed to characterize the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic potential of mutated epigenetic regulator genes in JMML. Methods: Tumor and matched buccal swab samples were collected from 35 JMML patients, and whole-exome sequencing was performed. Somatic variants were called with GATK-Mutect2 and annotated with ANNOVAR. maftools and OncodriveCLUST were used for mutational profiling, co-occurrence analysis, driver gene identification, and protein domain mapping. Drug–gene interactions were explored using DGIdb, mutational signatures for genes were characterized by MutationalPatterns, and functional enrichment analysis was performed by the clusterProfiler package. Results: A total of 28 variants were detected in epigenetic regulator genes, with missense mutations being the most common class of variants and a C>T nucleotide substitution pattern being the most frequent. EP300, SETD2, and DNMT3B were the genes most frequently altered, with 8.57% of cases each, followed by ASXL1, BCORL1, ATRX, KMT2A, and TET2 (5.71% each). Driver gene analysis identified ASXL1 as the top candidate driver gene, followed by BCORL1, EP300, and SETD2. Functional enrichment analysis revealed a high number of genes involved in chromatin organization, histone modification, transcriptional regulation, and oncogenic signaling pathways. The mutational signatures identified were SBS5-like, which are dominated by C>T and T>C transitions, indicating endogenous mutational processes. Analysis of drug–gene interactions revealed KMT2A, EP300, and ATRX as the most interconnected and potentially actionable therapeutic targets. Conclusions: This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis.
Abstract Introduction Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by overproduction of myeloid lineages. Driver mutations in JAK2 , CALR , and MPL account for most cases; however, additional somatic mutations contribute to disease heterogeneity, prognosis, and therapeutic response. Next-generation sequencing (NGS) enables comprehensive genomic profiling of these alterations. Objectives This article ails to characterize the mutational landscape of MPNs in a large Indian cohort using targeted NGS. Materials and Methods A total of 1,000 patients with clinically suspected MPNs were analyzed using DNA- and RNA-based NGS assays. Genomic DNA from peripheral blood or bone marrow samples underwent targeted library preparation and sequencing on Illumina and Thermo Fisher platforms. Bioinformatic analysis identified single-nucleotide variants, insertion–deletions, and clinically relevant gene fusions. Results Somatic alterations were detected in 490 patients. JAK2 V617F was the most frequent mutation (256 cases; 52.9%), followed by CALR exon 9 indels (50 cases; 11.1%) and MPL mutations (24 cases; 5.3%). Rare JAK2 exon 12 variants were identified in seven cases. Additional mutations included TET2 (94 cases; 20.9%), ASXL1 (53 cases; 11.8%), and SRSF2 (44 cases; 9.8%). RNA sequencing detected clinically relevant fusions including BCR::ABL1 , FIP1L1::PDGFRA , and ETV6::PDGFRB . Conclusion This large NGS-based study highlights the genetic heterogeneity of MPNs in an Indian population and supports the clinical utility of integrated genomic profiling for molecular diagnosis and risk stratification.
Arpan Mehta, Sagar Desai, Juhi Patel et al.· Indian Journal of Medical an...· 0 citations
Germline variants in leukemia predisposition genes are increasingly detected in pediatric patients. Nevertheless, the rare variants identified in diagnostic samples may be misinterpreted without variant-level functional evaluation and cautious clinical interpretation. Whole-exome sequencing was performed on 28 individuals from five kindreds in which at least two children developed acute leukemia. Results identified a rare ETV6 variant, c.604C > G (p.Arg202Gly), in monozygotic twins with ETV6::RUNX1-positive B-cell precursor acute lymphoblastic leukemia. To support variant interpretation, HeLa-cell populations stably expressing FLAG-tagged wild-type ETV6 and p.Arg202Gly and the known loss-of-function control p.Pro214Leu were established. Subcellular localization was assessed via immunofluorescence microscopy with quantitative scoring. Transcriptional repression was evaluated using luciferase reporter assays driven by ETV6 target promoters (MMP3 and PF4). p.Arg202Gly predominantly showed nuclear localization comparable to WT, whereas p.Pro214Leu was enriched in the cytoplasm. In the reporter assays, similar to WT, p.Arg202Gly retained repression activity. Meanwhile, p.Pro214Leu failed to repress both reporters. The in-silico prediction of nuclear export sequences suggested an additional export signal in p.Pro214Leu, but not in p.Arg202Gly. Collectively, these findings indicate that p.Arg202Gly behaves as WT-like in the assays performed and do not support a loss-of-function effect. Our study emphasizes the importance of variant-level functional assessment for rare ETV6 variants to inform clinical interpretation and avoid overestimation of pathogenicity.
Ai Yamada, Shun Nagasawa, Midori Nakagawa et al.· Human Cell· 0 citations
Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma characterized by heterogeneous clinical courses despite a common pathobiological initiating event. In this work we explore the genomic variants that characterize MCL and integrate transcriptomic data to comprehensively describe MCL biology. We performed whole exome sequencing (WES) on 28 tumor-normal pairs (lymph node and skin, respectively), as well as whole genome sequencing (WGS) and RNA sequencing on subsets of samples. We used established DNA and RNA analysis pipelines to detect single-nucleotide variants (SNV) and indels, structural variants, copy-number alterations, and RNA fusions. The canonical t(11;14)(q13;q32) CCND1::IGH translocation was detected in 8 of 10 WGS samples. Structural variant analysis additionally identified recurrent rearrangements involving KMT2A and PAFAH1B2. SNV and indel analyses revealed frequent mutations in ATM, TP53, CCND1, IGH, and NOTCH1. ATM exhibited diverse variant classes, including missense mutations, frameshift mutations, deletions, and duplications, while all detected NOTCH1 mutations were predicted loss-of-function frameshift variants. Copy-number analysis identified recurrent losses affecting DNA damage response genes, including TP53 and ATM, and recurrent gains involving transcriptional regulators and oncogenic signaling genes. Integrated pathway analysis demonstrated enrichment of transcriptional misregulation, DNA repair, PI3K/AKT signaling, and interleukin signaling pathways. We also identified recurrent alterations in candidate genes, including ASXL1, suggesting additional mechanisms of epigenetic dysregulation in MCL. Together, these findings provide a comprehensive description of somatic alterations in MCL and demonstrate that diverse genomic lesions converge on common pathways involved in genomic instability, transcriptional regulation, and tumor survival.
Charlz Nithin Jerold, Brian V. Li, Matthew Mosior et al.· medRxiv· 0 citations
Functional evidence is provided to fine-tune the classification of these SAMD9L variants and significantly advance the understanding of the molecular mechanisms by which SAMD9L variants drive inherited myeloid neoplasms.
E. Vuelta, A. Liquori, M. Morín et al.· British Journal of Haematolo...· 0 citations
PURPOSE
The clinical implications of distinct SMARCA4 alteration classes remain incompletely defined. We performed a pan-cancer analysis to characterize SMARCA4 mutation classes and their associations with allelic status, genomic context, and therapeutic outcomes.
PATIENTS AND METHODS
We analyzed 68,920 tumor-normal paired samples sequenced with the MSK-IMPACT next-generation sequencing assay between 2015 and 2023. Oncogenic or likely oncogenic SMARCA4 alterations were curated using OncoKB and classified based on prior functional and structural literature. Allele-specific copy number, ploidy, fraction of genome altered, loss of heterozygosity, and whole-genome doubling were calculated. Clinical outcomes were evaluated in selected tumor cohorts treated with platinum-based therapy or immune checkpoint blockade.
RESULTS
SMARCA4 alterations were most frequent in thymic epithelial tumors (10.7%), non-small cell lung cancer (NSCLC; 7.1%), bladder cancer (5.6%), and cervical cancer (5%). Class 1 and class 2 alterations occurred in 2.9% and 0.7% of tumors, respectively. Distinct patterns of genomic complexity, co-occurring alterations, and mutational signatures were observed across tumor types based on SMARCA4 alteration allelic state and class. In a phase I trial of the BRM degrader PRT3789, patients with monoallelic class 2 SMARCA4 alterations and preserved BRG1 expression saw clinical benefit, including one who attained a complete response.
CONCLUSIONS
SMARCA4 alteration class and allelic status define biologically and clinically distinct subsets of tumors. These findings support incorporating allelic status and functional mutation class into patient selection strategies for emerging BRM-targeted therapies.
M. Repetto, M. Gormally, Jason Chang et al.· Clinical Cancer Research· 0 citations
Objective: Testicular germ cell tumors (TGCTs) represent the most prevalent solid malignancy in young adult males. Despite multimodal treatment advancements, the molecular drivers of their aggressive biological behavior and subtype-specific differences remain insufficiently understood. Methods: This integrative in silico study utilized the cBioPortal platform to analyze Cancer Genome Atlas Pan-Cancer Atlas dataset. We examined genomic, transcriptomic, and proteomic data from a cohort of 149 TGCT patients to characterize mutation frequencies and structural variants across seminoma and non-seminomatous germ cell tumor subtypes. Results: Our analysis identified three principal genes with significant alteration frequencies: KIT (13%), KRAS (8%), and PTMA (5%). KIT and KRAS mutations demonstrated a marked subtype-specific distribution, with KRAS mutations observed exclusively in seminomas. In contrast, PTMA alterations displayed a broader distribution across multiple histologies, including mixed germ cell tumors and embryonal carcinomas. Additionally, we identified structural variants in genes such as TTC28, ACOT7, and CMSS1, highlighting the complexity of the TGCT genomic landscape. Conclusion: Our findings underscore the utility of integrative multi-omics analysis in elucidating the molecular background of TGCTs. The distinct association of KRAS and KIT with the seminomatous lineage, alongside the broad histological distribution of PTMA, provides novel insights into tumor biology. These molecular signatures may contribute to improved diagnostic precision and the development of tailored therapeutic interventions for patients with TGCT.
Begüm Çalım Gürbüz· Trends in Surgical Sciences· 0 citations
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