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Results for “Comprehensive genomic profiling”

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PubMed2004

Comprehensive gene expression analysis of the response to straight-chain alcohols in Saccharomyces cerevisiae using cDNA microarray.

AIMS: The purpose of this study was to examine the gene expression profiles of yeast Saccharomyces cerevisiae subjected to straight-chain alcohols. METHODS AND RESULTS: Lipophilic alcohols with high log Pow values were more toxic to yeast than those with low log Pow values. Morphological changes after exposure to ethanol, 1-pentanol, 1-octanol were observed, whereas n-pentane as a model hydrocarbon affected the surface of the outer membrane, with little change in organelles. Using cDNA microarrays, quite a few up-regulated gene categories were classified into the category 'cell rescue, defence and virulence' by ethanol, and the category 'energy' and 'metabolism' by 1-pentanol. Meanwhile, the characteristic genes up-regulated by n-pentane were not observed, and the expression profile was distantly related to ethanol, 1-pentanol and 1-octanol. CONCLUSIONS: This study suggests that gene expression profiles at the whole genome level were intimately associated with the cell growth inhibition and morphological changes by straight-chain alcohols with differing log Pow values. SIGNIFICANCE AND IMPACT OF THE STUDY: The study of comprehensive gene expression profiles by cDNA microarrays elucidates the straight-chain alcohol adaptation mechanisms.

1-Octanol↗

PubMed2024

Genomic profiling and expanded use of targeted anticancer drugs in solid cancers with exhausted evidence-based treatment options (PRECODE): study protocol of a prospective, non-randomized, cohort study.

BACKGROUND: Genomic profiling of advanced solid cancer in patients with no further evidence based standard treatment options is a novel approach to identify potential experimental treatment options based on specific genomic alterations. Due to the expected short survival of these patients timely assessment of potential druggable targets is critical to minimize the risk of deterioration during the analysis. The primary objective of this prospective study is to evaluate the turnaround time for genomic profiling and the clinical investigational procedures. The secondary objectives are to investigate how often genomic alterations in tumor tissue gives rise to a matched treatment offer and evaluate the clinical outcome. METHODS: The PRECODE study is a prospective, non-randomized, single-center cohort study conducted at Departments of Oncology and Pathology, Odense University Hospital, Denmark. Enrollment between March 1, 2019 and December 31, 2024. Eligibility criteria are age ≥ 18 years, written informed consent, advanced solid tumors, exhausted treatment options, ECOG performance status 0-2, adequate organ function and life expectancy ≥ 3 months. A core needle biopsy is analyzed by next generation sequencing using a pan-cancer comprehensive panel. Results are discussed weekly at institutional/local and national multidisciplinary tumor boards. DISCUSSION: Strategies and methods for genomic profiling of advanced solid cancers differ. Rapid analysis and interpretation of sequencing data are key to avoiding delays in initiation potential experimental treatments, as these late-stage patients may quickly deteriorate. Although a highly optimized setup with fast-track clinical evaluation and genomic profiling has been established a subset will not be offered a targeted treatment due to deterioration. Local and national multidisciplinary teams have been established to optimize individualized treatment decisions. After genomic profiling a subset of patients will take part in clinical trials, which will constrain the reporting of overall survival or progression free survival. TRIAL REGISTRATION: Danish Ethics Committee, Projekt-ID: S-2018014, date of approval: 27- FEB- 2019) Danish Data Protection Agency (Journal no: 18/58329, date of approval: 23-NOV-2018). CLINICALTRIALS: gov Identifier: NCT05385081 (retrospectively registered).

Humans↗

PubMed2026

Whole genome sequencing reveals a specific microbiota in subglottic stenosis C. acnes may contribute to inflammation.

PURPOSE: Subglottic stenosis (SGS) progressively reduces the airway below the vocal folds. The cause is not known and there is a recurrent need of surgical treatment. Including all phenotypes, SGS affects 1/400 000/yr, with a female dominance. Previous studies have revealed a possible role of the Mycobacterium complex in SGS development. Our hypothesis is that microbiota is associated with the inflammation in SGS, if true it might affect the prevailing treatment options. METHODS: This prospective cross-sectional study included biopsies from 34 patients with subglottic stenosis, collected between 2020 and 2023. Nucleic acids were extracted from the tissue samples and analysed using whole genome sequencing. Microbial composition was characterized using taxonomic profiling of sequencing data. Species with sufficient read counts were selected for further validation using sequence alignment methods to ensure accuracy of identification. RESULTS: Using the most comprehensive form of genomic testing currently in clinical use, we present curated and stable data on the presence of Cutibacterium acnes in 28 out of the 34 cases. CONCLUSION: Cutibacterium acnes may serve as a driver of the inflammation characterizing SGS and should be considered in therapeutically oriented future studies.

Cutibacterium acnes↗

PubMed2004

Kinome profiling for studying lipopolysaccharide signal transduction in human peripheral blood mononuclear cells.

The DNA array technique allows comprehensive analysis of the genome and transcriptome, but the high throughput array-based assessment of intracellular signal transduction remains troublesome. The goal of this study was to test a new peptide array technology for studying the activity of all kinases of whole cell lysates, the kinome. Cell lysates from human peripheral blood mononuclear cells before and after stimulation with lipopolysaccharide were used for in vitro phosphorylation with [gamma-33P]ATP arrays consisting of 192 peptides (substrates for kinases) spotted on glass. The usefulness of peptide arrays for studying signal transduction was demonstrated by the generation of the first comprehensive description of the temporal kinetics of phosphorylation events induced by lipopolysaccharide stimulation. Furthermore analysis of the signals obtained suggested activation of p21Ras by lipopolysaccharide, and this was confirmed by direct measurement of p21Ras GTP levels in lipopolysaccharide-stimulated human peripheral blood mononuclear cells, which represents the first direct demonstration of p21Ras activation by stimulation of a Toll receptor family member. Further confidence in the usefulness of peptide array technology for studying signal transduction came from Western blot analysis of lipopolysaccharide-stimulated cells, which corroborated the signals obtained using peptide arrays as well as from the demonstration that kinase inhibitors effected peptide array phosphorylation patterns consistent with the expected action of these inhibitors. We conclude that this first metabolic array is a useful method to determine the enzymatic activities of a large group of kinases, offering high throughput analysis of cellular metabolism and signal transduction.

Amino Acid Sequence↗

PubMed2025

Comparison of actionable alterations in cancers with kinase fusion, mutation, and copy number alteration.

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

Humans↗

PubMed2004

Functional genomics and prognosis in sarcoidosis--the critical role of antigen presentation.

BACKGROUND: Sarcoidosis is a systemic disorder of unknown cause, highly variable phenotype and unpredictable outcome. Antigen processing, inflammatory response and immunomodulation appear critical to development and prognosis of the disease. METHODS: We performed a comprehensive genomic analysis, applying high-density human GeneChip probe arrays (HUG95A, Affymetrix Inc.) for gene expression profiling from peripheral blood of patients with acute pulmonary sarcoidosis (n = 12) and matched healthy controls (n = 12), mean age 36 +/- 12 and 33 +/- 10 years respectively. RESULTS: At follow-up (18 [15-24] months), 7 patients had self-limited disease and 5 had persistent disease. Significantly different expression comparing patients and controls was identified for 1,860 (14.9%) and 729 (5.8%) gene products at p = 0.05 and p = 0.01 levels respectively. Genes closely associated with persistent disease included HLA-DRB1*1501 DQB1*0602, TNFA, NFKB, cyclic AMP-responsive element modulator (CREM) and T-cell activation marker CD69. IL1B, IL8, growth related (GRO)-beta/-gamma and CCR 2,5,6 were closely associated with self-limited disease. CONCLUSION: We hypothesize that, in self-limited disease, greater effector cell activation leads to successful antigen elimination/tolerance, whereas HLA-DRB1*1501 DQBI*0602-mediated, probably defective/partial T-lymphocyte activation results in an inefficient primary immune response, antigen intolerance and persistent disease.

Adult↗

PubMed2001

Disease fingerprinting with cDNA microarrays reveals distinct gene expression profiles in lethal type 1 and type 2 cytokine-mediated inflammatory reactions.

Development of polarized immune responses controls resistance and susceptibility to many microorganisms. However, studies of several infectious, allergic, and autoimmune diseases have shown that chronic type-1 and type-2 cytokine responses can also cause significant morbidity and mortality if left unchecked. We used mouse cDNA microarrays to molecularly phenotype the gene expression patterns that characterize two disparate but equally lethal forms of liver pathology that develop in Schistosoma mansoni infected mice polarized for type-1 and type-2 cytokine responses. Hierarchical clustering analysis identified at least three groups of genes associated with a polarized type-2 response and two linked with an extreme type-1 cytokine phenotype. Predictions about liver fibrosis, apoptosis, and granulocyte recruitment and activation generated by the microarray studies were confirmed later by traditional biological assays. The data show that cDNA microarrays are useful not only for determining coordinated gene expression profiles but are also highly effective for molecularly "fingerprinting" diseased tissues. Moreover, they illustrate the potential of genome-wide approaches for generating comprehensive views on the molecular and biochemical mechanisms regulating infectious disease pathogenesis.

Animals↗

PubMed2004

Lectin-based structural glycomics: glycoproteomics and glycan profiling.

Structural glycomics (SG) plays a fundamental part of concurrent glycobiology aiming at comprehensive elucidation of glycan functions ( i.e. , functional glycomics) in the context of post-genome sciences. The SG project started in April 2003 and will continue for 3 years in the framework of NEDO (New Energy and Industrial Technology Organization) under the METI (the Ministry of Economy, Trade, and Industry), Japan. The main purpose of the project is the development of high-throughput and robust machines, which should greatly contribute to the structural analysis of complex glycans. In this chapter, 2 major research items, i.e. , (1) glycoproteomics, which enables comprehensive analysis of glycoproteins, and (2) "glycan profiling" by means of lectins, are described. For the latter, frontal affinity chromatography has been adopted as a starting tool for comprehensive analysis of the interaction of 100 lectins and 100 oligosaccharides under the concept of "hect-by-hect," which refers to 100 x 100.

Animals↗

PubMed2006

Wide genomic analysis of human endometrial receptivity: new times, new opportunities.

Microarray technology has broadened the insight into many research fields allowing scientists to analyse the expression of many genes in quick and efficient experiments aimed at translating these findings into clinical applications. In reproductive medicine, researchers have exploited microarrays to increase understanding of the molecular mechanisms involved in endometrial receptivity and how a possible therapeutic translation can be feasible. In the last 4 years, several studies have focused on the genomics of the human endometrium in different physiological and pathological conditions, and these studies have generated a large amount of information about the regulation and dysregulation of the window of implantation (WOI) genes in fertile, subfertile and refractory conditions. However, the key molecules/mechanisms in endometrial receptivity remain to be elucidated. In this comprehensive review, we have analysed the available results obtained in our own and other laboratories, defining the genomic profile of the receptive endometrium in different situations and its possible clinical application.

Animals↗

PubMed2001

[A model for clinical study based on genome science--trials in disorders of the immune system and allergies].

Disorders of the immune system, such as allergies, have multi-factorial etiologies that include both genetic and environmental components. The recent advances in genome science have facilitated two strategies for studying the genetic basis of disease: (1) systematic analysis of gene expression profiles and (2) comprehensive analysis of gene variations, such as polymorphisms. Here, we describe a unique research institute, Genox Research Inc., that can relate the clinical profile of a patient to genotyping and molecular profiling. Systematic gene expression analyses using differential display have been performed to explore genes related to allergy, and revealed 93 differentially expressed candidate genes in T-cells. Also, a single nucleotide polymorphism(SNP) analysis project has been designed to mine disease-related and/or drug-response-related genes involved in allergic disorders using biochip technologies. As exemplified above, clinical studies based on these applications of genome science would be of considerable value in clarifying our understanding of multi-gene disorders.

Gene Expression Profiling↗

PubMed2026

Epigenetic Liquid Biopsy Enables Universal Mutation-Agnostic Molecular Surveillance for High-Risk Neuroblastoma.

PURPOSE: Liquid biopsy monitoring in pediatric solid tumors is limited by low mutational burden and lack of trackable genomic drivers. We sought to develop a mutation-agnostic, methylation-based liquid biopsy framework enabling universal molecular surveillance of high-risk neuroblastoma. EXPERIMENTAL DESIGN: Using whole-genome Oxford Nanopore Technologies sequencing of high-risk neuroblastoma tumors, we compared tumor-derived methylation profiles with a comprehensive atlas of normal human cell types and identified 72 neuroblastoma-specific differentially methylated regions (meNBL) that were reliably detectable in cell-free DNA (cfDNA). Marker robustness and specificity were validated using independent neuroblastoma methylation datasets and assessed against methylation profiles from other cancer types. We established neuroblastoma as a distinct methylation entity within the reference atlas by integrating a panel of 25 meNBLs, enabling quantitative estimation of tumor-derived cfDNA. Assay performance was evaluated across diagnostic, remission, relapse, and healthy control samples and compared with mutation-based and copy number-based approaches. RESULTS: Neuroblastoma-derived cfDNA was consistently detected at diagnosis and relapse but was absent in healthy controls and during confirmed remission. Methylation-based deconvolution demonstrated high specificity, with no detectable background signal in controls, and improved performance relative to copy number-based tumor fraction estimation. Longitudinal profiling enabled early molecular detection of relapse and reliable disease monitoring. CONCLUSIONS: We establish a robust, mutation-independent methylation-based liquid biopsy strategy for neuroblastoma that enables accurate, quantitative disease monitoring across all high-risk patients, including those lacking trackable genomic alterations. This approach supports the clinical translation of methylation-based cfDNA deconvolution as a broadly applicable platform for pediatric precision oncology.

Humans↗

PubMed2006

From genome to proteome in tumor profiling: molecular events in colorectal cancer genesis.

Biomedical research has advanced rapidly in recent years with the sequencing of the human genome and the availability of technologies such as global gene and protein expression profiling using different chip platforms. However, this progress has not yet been transferred to the bedside. While detection of cancer at early stages is critical for curative treatment interventions, efficient diagnostic and therapeutic markers for the majority of malignancies still seem to be lacking. Comprehensive tumor profiling has therefore become a field of intensive research aiming at identifying biomarkers relevant for improved diagnostics and therapeutics. This chapter will demonstrate a genomic and proteomic approach while focusing on tumor profiling during colorectal cancer development.

Animals↗

PubMed2026

Comprehensive In Vitro, Genomic, Microbiota, and Subacute Toxicological Safety Characterization of Lactiplantibacillus plantarum ATA-LPC98052.

BACKGROUND: Lactiplantibacillus plantarum is a widely studied probiotic species; however, probiotic characteristics and safety profiles are strain-specific, requiring independent evaluation. This study characterized Lactiplantibacillus plantarum ATA-LPC98052 as a candidate probiotic raw material. METHODS: ATA-LPC98052 was evaluated for hemolysis, acid/bile tolerance, Caco-2 adhesion, cytotoxicity, and storage stability. Subacute oral safety was assessed in Wistar rats by gavage for 28 days at 1.2 × 1011 CFU/kg/day; the study design incorporated selected principles of OECD Test Guideline 407. Clinical, hematological, biochemical, organ-weight, and macroscopic endpoints were evaluated. Fecal microbiota was analyzed by 16S rRNA sequencing; WGS was used for taxonomic confirmation and genomic safety screening. RESULTS: ATA-LPC98052 was γ-hemolytic and maintained 60% viability at pH 1.5 and 96% at pH 5.0, while viability ranged from 74% to 82% across 0.1-0.5% bile salt concentrations. Caco-2 cell viability was 99%, adhesion exceeded 90%, and the lyophilized preparation remained stable for 15 months, maintaining 9.6 log10 CFU/g. Repeated oral administration caused no mortality or consistent treatment-related toxicological pattern. Longitudinal microbiota analysis showed no significant treatment × time effects on alpha diversity or Bray-Curtis community structure, and no genus-level MaAsLin2 association was FDR-significant. WGS confirmed L. plantarum identity and no contamination; ResFinder detected no acquired antimicrobial resistance determinants meeting specified thresholds, whereas CARD/RGI identified low-identity qacJ and vanY homologs requiring cautious interpretation. CONCLUSION: ATA-LPC98052 demonstrated favorable in vitro probiotic characteristics, technological stability, gut microbiota-modulating potential, and a favorable subacute safety profile under the tested conditions; however, microbiota findings were exploratory, and phenotypic MIC testing remains warranted.

Animals↗

PubMed2004

Monitoring of stress responses.

New developments in the RNA analysis techniques now enable a comprehensive view on the bacterial physiology under bioprocess conditions. The DNA-chip technology allows a genome wide transcriptional profiling of bacterial cells, whose genome sequence is available. Although the analyses of microbial bioprocesses have still been somewhat limited to date, this technique has already been successfully applied in different laboratories for the investigation of stress responses of selected industrially relevant bacterial hosts. Transcriptome analyses in combination with high resolution two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry have been extensively applied for the description of general and specific stress and starvation responses of Escherichia coli and Bacillus subtilis. The consideration of bacterial stress and starvation responses is of crucial importance for the successful establishment of an industrial large scale bioprocess. Stress genes can be used as marker genes in order to monitor the fitness of industrial bacterial hosts during fermentation processes. This chapter gives an overview of current RNA analysis techniques. The bacterial stress and starvation responses, which are of potential importance for industrial microbial bioprocesses are summarised.

Adaptation, Physiological↗

PubMed2026

Innovative advances and clinical applications of cell-free DNA methylation detection technologies.

Advances in DNA methylation detection technologies have promoted disease-related cell-free DNA (cfDNA) analysis. CfDNA methylation profiling has the potential to serve as a promising clinical tool for early disease diagnosis. However, current detection technologies suffer from high costs, complex operational procedures, and insufficient sensitivity for low-input samples. Moreover, the definitive validation of its clinical value still awaits robust evidence from high-quality confirmatory studies. Therefore, this review begins by mapping the historical evolution of cfDNA methylation, followed by a comparison of the traditional approaches and recent breakthroughs in cfDNA methylation analysis. Specifically, this review systematically examines the two major strategies: the ones based on bisulfite-dependent DNA modification and the bisulfite-free methods, including the techniques for whole-genome methylation profiling and methods targeting specific genomic regions. Additionally, to evaluate the clinical application potential of these methods, this review comprehensively describes the details of these technologies, such as sample input requirements and sensing accuracy in detecting clinical samples. The future development of cfDNA methylation detection will focus on clinical translation, integrating technical innovations with the demands for efficient clinical diagnosis. We believe this review will help researchers select methods tailored to sample availability and clinical applicability.

Humans↗

PubMed1997

Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment.

For an understanding of the aberrant biology seen in mouse mutations and identification of more subtle phenotype variation, there is a need for a full clinical and pathological characterization of the animals. Although there has been some use of sophisticated techniques, the majority of behavioral and functional analyses in mice have been qualitative rather than quantitative in nature. There is, however, no comprehensive routine screening and testing protocol designed to identify and characterize phenotype variation or disorders associated with the mouse genome. We have developed the SHIRPA procedure to characterize the phenotype of mice in three stages. The primary screen utilizes standard methods to provide a behavioral and functional profile by observational assessment. The secondary screen involves a comprehensive behavioral assessment battery and pathological analysis. These protocols provide the framework for a general phenotype assessment that is suitable for a wide range of applications, including the characterization of spontaneous and induced mutants, the analysis of transgenic and gene-targeted phenotypes, and the definition of variation between strains. The tertiary screening stage described is tailored to the assessment of existing or potential models of neurological disease, as well as the assessment of phenotypic variability that may be the result of unknown genetic influences. SHIRPA utilizes standardized protocols for behavioral and functional assessment that provide a sensitive measure for quantifying phenotype expression in the mouse. These paradigms can be refined to test the function of specific neural pathways, which will, in turn, contribute to a greater understanding of neurological disorders.

Animals↗

PubMed2026

Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.

Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationship to blast-phase chronic myeloid leukemia. In this multicenter study of 44 patients, 86.4% had B/myeloid MPAL, 72.7% showed lymphoid predominance, 40.9% had complex karyotypes, and 68.3% harbored somatic mutations, most commonly RUNX1 mutations (46.3%). RUNX1 mutations frequently co-occurred with acute myeloid leukemia (AML)-associated alterations, whereas DNMT3A, TET2, and BCORL1 mutations were restricted to RUNX1-mutated cases. In contrast, acute lymphoblastic leukemia (ALL)-associated alterations (IKZF1 mutation/deletion and ETV6 mutations) were confined to RUNX1-wild-type patients. TP53 and signaling pathway mutations (NRAS, KRAS, PTPN11, and FLT3) were not detected. Forty-two patients received induction chemotherapy and/or immunotherapy combined with tyrosine kinase inhibitors: 74.2% of lymphoid-predominant patients and 63.6% of myeloid-predominant patients received ALL- and AML-type therapies, respectively. Ten patients relapsed, and 2 had primary refractory disease; some exhibited a dynamic shift in predominant lineage immunophenotype, chromosomal alterations, and somatic mutations at the relapse or refractory stage. The overall remission rate was 86.8%, with no significant differences across ALL-, AML-, or hybrid-type regimens. After a median follow-up of 24.2 months, the median overall survival was 52.5 months. Complex karyotype was associated with inferior overall survival compared with cases lacking additional chromosomal alterations (P = .02), whereas RUNX1 mutations were not. No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without chronic myeloid leukemia-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.

Adolescent↗

PubMed2026

Integrated Clinicopathologic and Multiomic Profiling Reveals MEIS1-Rearranged Sarcoma as a Distinct Entity With 2 Prognostic Subgroups.

Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age, 41 years; range, 6-58 years), arising mainly in the uterus/vagina (n = 12), vulva/perineum (n = 4), bone (n = 2), and kidney (n = 2), with a median size of 9 cm (range, 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising 2 subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The 2 DNA methylation (Meth) subgroups correlated with differences in genome-wide copy number variation (CNV) status (Meth-CNV high vs Meth-CNV low), with Meth-CNV high tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (P = .027) and disease-free survival (median, 5 vs 99 months; P = .017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The 2 methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Humans↗