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PubMed2026

Integrative transcriptomic, spatial and functional-genomic analysis identifies a UFMylation-related vascular-stromal program and prioritizes WWTR1 in glioblastoma.

Glioblastoma (GBM) contains spatially organized stress-adaptive and vascular niches. Because transcript abundance does not measure UFM1 conjugation, we asked whether a UFMylation-related transcriptional axis identifies a reproducible tissue program and alters candidate prioritization. In 518 unique primary TCGA-GBM tumors profiled on the Affymetrix HT Human Genome U133A array, weighted gene co-expression network analysis of 8,000 variable genes yielded 12 modules. The 278-gene green module ranked first across nine prespecified traits (mean |r|=0.637). Direct overlap comprised 1/3 measurable UFMylation-core, 5/19 ER-stress/UPR, and 2/15 proteostasis genes; after excluding overlapping genes, correlations with the green eigengene remained significant (r = 0.373, 0.831, 0.639, and 0.699 for UFMylation-core, ER-stress/UPR, proteostasis, and composite scores, respectively). The green score was associated with overall survival per standard-deviation increase (HR 1.17, 95% CI 1.07-1.28), although clinical adjustment attenuated the estimate. In a 10-sample single-cell dataset, sample-level scores were higher in pericytes and endothelial cells than in malignant cells. Donor-aware IvyGAP analysis supported regional organization, whereas one Visium section showed stronger concordance with ER-stress/UPR and mesenchymal scores than with the UFMylation-core score. CellChat indicated pathway-selective rather than global remodeling of inferred vascular communication. Layer ablation moved WWTR1 from rank 48 using WGCNA alone to rank 4 overall and rank 1 among non-common-essential genes after cross-platform integration. These findings define an ER-stress/mesenchymal-weighted, UFMylation-related vascular-stromal transcriptional association and nominate WWTR1 for experimental testing.

Humans↗

PubMed2026

Lipid Metabolism-related lncRNA Model Identifies AC026412.3 as a Driver of Fatty Acid β-oxidation in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Dysregulated lipid metabolism contributes to hepatocellular carcinoma (HCC) progression, but the prognostic value and mechanistic roles of lipid metabolism-related long noncoding RNAs (LRLs) remain insufficiently characterized. This study aimed to construct and validate an LRL-based prognostic model and to investigate the biological function and metabolic mechanism of AC026412.3 in HCC. METHODS: Transcriptomic and clinical data from the The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort were analyzed to identify LRLs based on their correlation with curated lipid metabolism genes. Differential expression, univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were performed to construct a prognostic signature, which was evaluated using Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) analyses. Functional enrichment analyses Gene Ontology [GO], Kyoto Encyclopedia of Genes and Genomes [KEGG] and gene set enrichment analysis [GSEA], mutation profiling, tumor mutational burden, immune infiltration estimation, and consensus clustering were applied to characterize associated features. A key LRL was identified through integrated bioinformatic screening and prioritization. Its biological role was assessed by quantitative reverse transcription polymerase chain reactionq (RT-PCR), western blotting, BODIPY staining, colony formation, Transwell assays, and xenograft models. RNA sequencing followed by pathway enrichment analysis was conducted to explore underlying mechanisms. RESULTS: A three-LRL signature (AL031985.3, NRAV, and AC026412.3) stratified HCC patients into distinct risk groups with significantly different survival outcomes and demonstrated independent prognostic value. AC026412.3 was markedly upregulated in HCC and associated with poor prognosis. Functional assays demonstrated that AC026412.3 promoted proliferation, invasion, and tumor growth while reducing lipid accumulation. Mechanistically, AC026412.3 upregulated solute carrier family 22 member 5 (SLC22A5), enhanced fatty acid β-oxidation, and increased adenosine triphosphate (ATP) production, thereby driving metabolic reprogramming. CONCLUSIONS: This study establishes a robust LRL-based prognostic model and identifies AC026412.3 as a key regulator of lipid metabolic reprogramming via the SLC22A5-fatty acid β-oxidation axis, highlighting its potential as a biomarker and therapeutic target in HCC.

HCC↗

PubMed2026

Methylome Profiling of Cartilage Tumors: A Promising New Diagnostic Tool?

DNA methylation and copy number variation (CNV) profiling has emerged as a promising tool for the classification of bone and soft tissue tumors. We evaluated its utility in cartilage tumors, where distinguishing low-grade from high-grade conventional central chondrosarcomas (CSs) and atypical cartilaginous tumors (ACTs) from enchondromas (ECs) is a frequent diagnostic challenge, particularly on biopsy material. We analyzed 214 chondrogenic tumors, including ECs, ACTs, conventional CSs, dedifferentiated chondrosarcomas (DDCSs), and clear cell CSs, and determined their IDH1/2 mutation status. Unsupervised dimensionality reduction of genome-wide DNA methylation patterns revealed 4 clusters among IDH-mutant (MUT) tumors (IDH-MUT-1: mostly ECs and ACTs and some high-grade CSs; IDH-MUT-2: predominantly high-grade CSs; IDH-MUT-3: largely DDCSs; and IDH-MUT-SB: distinct skull base group with a markedly different methylation pattern) and 2 clusters among IDH-wild-type (WT) tumors (IDH-WT-1 and IDH-WT-2: both primarily high-grade CSs, with IDH-WT-2 showing higher tumor grade and more extensive CNVs). Clear cell CSs formed a separate cluster. The amount of CNVs, including loss of CDKN2A, increased with tumor grade, reflecting increased genomic instability during chondrosarcoma progression. Supervised classifiers trained separately, both on methylation and CNV data, and distinguished low-grade and high-grade cartilaginous tumors with area under the curve values of 0.87 to 0.97 and 85% to 90% accuracy. Furthermore, we tested whether DDCSs can be distinguished from metastatic carcinomas and other high-grade sarcomas of the bone. Across 246 reference samples, a supervised classifier achieved 97.2% accuracy (area under the curve, 99.8%) and correctly identified 30 of 32 DDCSs (93.8%). These results indicate that DNA methylation and CNV data analysis provide a valuable tool for distinguishing most low- and high-grade CSs, with additional utility also in differentiating DDCS from morphologic mimics.

cartilaginous tumors↗

PubMed2026

Methylation profiling in CNS tumor diagnostics: a single-centre real-world experience from Central Europe.

Genome-wide DNA methylation profiling has transformed neuro-oncology by providing an objective, machine learning-based taxonomy that mitigates interobserver variability and refines the histo-molecular criteria of the current WHO classification. We evaluate the real-world diagnostic performance and clinical utility of this modality in a prospective, consecutively accrued three-year cohort of 291 central nervous system (CNS) tumors across a mixed adult-pediatric population. Successful profiling was completed in 95.9% of cases. Using the Epignostix classifier, a high-confidence diagnostic match (calibrated score [CS] ≥ 0.84) was achieved in 70.3% of analyzable samples, while 26.5% returned lower-confidence scores (≥ 0.3 to < 0.84) and only 3.2% remained completely unclassifiable (CS < 0.3). When integrated into a comprehensive diagnostic framework, methylation profiling provided clinically useful results in 81.1% of cases, establishing diagnoses in 70 cases submitted for molecular subclassification and resolving diagnostic uncertainty or prompting major revisions in 149 histologically challenging tumors. Within truly ambiguous lesions, integration of methylome data dictated tumor grade modifications in 38.8% of cases (upgrading in 29.4% and downgrading in 9.4%), shifting patient risk stratification. Crucially, over half (52.7%) of the lower-confidence cases yielded meaningful clinical integration when supported by histomorphology and ancillary genetic or immunohistochemical markers, demonstrating that rigid score cutoffs should not dictate assay failure. Discrepant or misleading classifications occurred in 1.9%. Updating bioinformatic pipelines from version 11b4 to 12.8 rescued multiple ambiguous entries, increasing overall clinical utility to 84.1%. These findings demonstrate that integrating computational epigenomics with classical neuropathology enhances diagnostic precision, while highlighting the ongoing need for careful clinical-pathological correlation.

Central nervous system tumors↗

PubMed2026

Paired genomic profiling of primary tumor and lymph-node metastases identifies candidate prognostic features in penile squamous cell carcinoma.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited genomic data in Asian populations. Lymph node metastasis heavily dictates prognosis, yet molecular determinants of progression remain poorly understood. We aimed to characterize the genomic landscape and explore candidate prognostic genomic features using paired primary and metastatic PSCC tumors. PATIENTS AND METHODS: Targeted next-generation sequencing (437 cancer-related genes) was performed on primary tumors and matched lymph node metastases from 20 Chinese patients. Somatic alterations, intralesional heterogeneity, and tumor mutation burden (TMB) were analyzed and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: The most frequent primary tumor mutations included TP53 (45%) and TERT (40%). Notably, CCND1/FGF19 co-amplification (20% of cases) was associated with inferior DFS (P = .027) and showed a trend toward shorter OS (P = .050). Conversely, T-cell receptor (TCR) pathway alterations correlated with markedly improved survival. Comparing paired lesions revealed 59.8% shared alterations. Elevated TMB in metastases relative to matched primary tumors was significantly associated with poorer DFS (P = .008), while higher intralesional heterogeneity showed a trend toward worse OS. CONCLUSION: Paired profiling revealed broadly conserved genomic features together with lesion-specific divergence in PSCC. Recurrent CCND1/FGF19-containing 11q13 amplification, TCR pathway alterations, and elevated metastatic TMB warrant evaluation as potential prognostic features in larger, independently validated cohorts with integrated HPV and immune profiling.

Humans↗

PubMed2026

Identification of molecular subtypes in clear cell renal cell carcinoma based on chromatin regulators and tumor immune microenvironment profiling.

In the histological classification of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) accounts for the highest proportion and is the most common subtype. Despite advances in management, it continues to be associated with considerable incidence and mortality. Although surgery and systemic therapies are available, their efficacy is constrained by pronounced intratumoral heterogeneity and treatment resistance. Identifying robust biomarkers and clarifying the underlying biological mechanisms are therefore essential to improving diagnosis, risk stratification and therapeutic decision-making. In this work, we identified two ccRCC molecular subtypes displaying divergent chromatin regulator (CR) profiles and different clinical prognoses. Using the genes differentially expressed between these subgroups, we constructed a CR-related score (CRS) that effectively stratified patients according to survival. More analysis concluded that the low expression of CR was more linked with the immune-activated tumors, which encompassed the immune pathway enrichment, as well as the elevation of numerous immune cell subtypes. Moreover, elevated CRS was associated with improved immunotherapy responsiveness. Drug-sensitivity analyses nominated several candidate agents, and SMARCD3 knockdown in 786-O cells inhibited proliferation and migration and reduced sensitivity to masitinib. Collectively, these findings support the prognostic and therapeutic relevance of CR-related states in ccRCC and provide a framework for future experimental validation of chromatin-regulated tumor-immune interactions.

Humans↗

PubMed2026

Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma.

BACKGROUND: Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored. METHODS: Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers. RESULTS: Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions. CONCLUSIONS: This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

Humans↗

PubMed2026

Genomic profiling by circulating tumor DNA in patients with hormone receptor-positive/HER2-negative advanced breast cancer: Prevalence of actionable mutations across treatment lines.

INTRODUCTION: Plasma next-generation sequencing (NGS) is endorsed by ESMO as an alternative to tissue testing in advanced hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- mBC), particularly after progression on endocrine therapy plus CDK4/6 inhibitors. However, prospective real-world data across distinct therapeutic contexts remain limited. PATIENTS AND METHODS: In this prospective observational study conducted within a nationwide cancer network in Brazil, centralized plasma NGS, and tissue NGS when available, was performed in two independent cohorts: prior to initiation of first-line endocrine therapy in the metastatic setting (Cohort 1) and at progression on endocrine therapy plus a CDK4/6 inhibitor (Cohort 2). The primary objective was to evaluate plasma-detected ESR1 mutation prevalence across these therapeutic contexts, and secondarily to assess other actionable drivers detected by plasma or tissue NGS. RESULTS: Among 86 collected plasma samples, 72 (84%) had evaluable NGS results (Cohort 1, n = 37; Cohort 2, n = 35). ESR1 mutations were identified in 18.9% of patients in Cohort 1 and 40.0% in Cohort 2, mostly at low variant allele fractions (<0.5%), corresponding to an absolute prevalence difference of 21.1 percentage points (95% CI, -0.2 to 40.3; P value=0.07). When considering any actionable alteration detected by plasma, including ESR1, PIK3CA, AKT1, PTEN, BRCA1, BRCA2, and ERBB2, prevalences were 43.2% and 68.6%, respectively (P value=0.04). Only four patients had ESR1 mutations identified in tissue, three in metastatic samples. Plasma-tissue concordance was higher for PIK3CA mutations (85.1%). CONCLUSION: Plasma NGS identified clinically meaningful ESR1 mutation rates across both contexts, supporting guideline-endorsed plasma-based genomic profiling in HR+/HER2- mBC.

CDK4/6 inhibitors↗

PubMed2026

Comprehensive Clinicopathologic, Immunohistochemical, and Genomic Profiling of Sporadic Ampullary Somatostatin-producing D-cell Neuroendocrine Tumors Identifies Recurrent HRAS Hotspot Mutations.

Ampullary somatostatin-producing D-cell neuroendocrine tumors are rare neoplasms that may be associated with type 1 neurofibromatosis. The molecular features of sporadic ampullary somatostatin-producing D-cell neuroendocrine tumors (SAMSOM-NETs) remain poorly characterized. We performed an integrated morphological, immunohistochemical, and genomic analysis of a multicenter series of SAMSOM-NETs. Eleven cases were included (73% male; median age: 63 years). All six patients who underwent lymphadenectomy were staged as pN1, and liver metastases were found in three cases; however, no tumor-related deaths occurred (median follow-up: 104 months). Common histologic features that can pose diagnostic challenges in the differential diagnosis with adenocarcinoma included a tubulo-glandular architecture (100%), periodic Acid-Schiff (PAS)-positive intraluminal mucin (73%), MUC1 expression (100%), and carcinoembryonic antigen (45%) expression. All tumors exhibited dot-like cytoplasmic reactivity for cytokeratins (CK) CAM5.2 or CK AE1/AE3, and 82% were CK7-positive. ISL1 and PDX1 were diffusely expressed in all cases, while CDX2 was positive in 54% and ARX showed only focal expression in four tumors. Genomic profiling revealed microsatellite stability and low tumor mutational burden. Alterations in the RAS pathway, including HRAS mutations (4 cases, 36%), a KRAS mutation (1 case), and NF1 alterations (one case), were identified in 54% of cases and in all tumors with liver metastases. Additional molecular findings included a CDK12 splice-site alteration and an NTRK3::PRDM4 fusion. Potentially actionable alterations affecting kinase-related pathways were detected in 64% of tumors. Our findings support SAMSOM-NET as a peculiar neuroendocrine tumor subtype showing distinctive histologic and molecular characteristics with potential diagnostic and therapeutic implications.

Humans↗

PubMed2026

Fibrotubular Tumors of the Thyroid: An Emerging Thyroid Neoplasm Characterized by Distinctive Morphology and Recurrent OCLN::PRKCI Gene Fusions Spanning the Adenoma-Carcinoma Spectrum.

The histopathologic and genomic landscape of thyroid tumors is well characterized, although new genetic alterations and tumor types are being described. We present 2 cases of thyroid tumors originating from follicular cells that had highly unusual and distinct morphologic features and carried an OCLN::PRKCI gene fusion. These tumors were well circumscribed, encapsulated, and composed of irregularly shaped tubular and follicular structures surrounded by layers of distinct fibrocollagenous basement membrane material positive for type IV collagen and laminin; they showed no definitive nuclear features of papillary carcinoma. Importantly, whereas one of the tumors had no invasive growth, the other demonstrated tumor capsule invasion, compatible with the adenoma-carcinoma spectrum seen in thyroid follicular and oncocytic tumors. Gene expression profiles of these tumors differed from those of common types of papillary thyroid carcinoma. The unusual and reproducible histopathologic characteristics and unique molecular profiles of these tumors support their designation as a distinct type of thyroid neoplasm that exists in noninvasive and invasive forms and, therefore, can be designated as fibrotubular adenoma and carcinoma. Recognition of this distinct entity is important for improving diagnostic accuracy and avoiding overtreatment of this likely indolent type of thyroid neoplasia.

Humans↗

PubMed2026

Incidental MSH6 Germline Pathogenic Variant Identified through Tumor-only Comprehensive Genomic Profiling in a Patient with Small Cell Lung Cancer.

A 55-year-old woman was diagnosed with limited-disease small cell lung cancer (LD-SCLC) after incidental detection of a lung nodule. First-line chemotherapy achieved partial response, but recurrence occurred after one year. During second-line therapy, comprehensive genomic profiling (CGP) revealed a germline MSH6 frameshift mutation. Although lung tumor immunohistochemistry showed the retained expression of mismatch repair (MMR) protein, a prior colon cancer specimen showed the loss of MSH6 expression and deficient MMR expression. Germline genetic testing confirmed Lynch syndrome. Cascade testing identified the same mutation in her daughter. This case outlines a tumor-to-germline workflow with testing of at-risk relatives and highlights the importance of prudent interpretation of presumed germline variants.

Humans↗

PubMed2026

Real-World Testing Landscape and Costs of Companion Diagnostics and Comprehensive Genomic Profiling Across Nine Solid Tumors in Japan: A 10-Year Analysis.

INTRODUCTION: This study aimed to examine utilization, testing sequences, and associated genomic testing costs of companion diagnostics (CDx) and comprehensive genomic profiling (CGP) among Japanese patients with nine representative solid tumors. METHODS: This retrospective study used anonymized data, from Medical Data Vision Co., Ltd. (MDV; January 2015-March 2025) and JMDC Inc. (JMDC; January 2015-January 2025), for patients with solid tumors of nine cancer types who underwent CDx and/or CGP testing or received any cancer treatment. Patient demographics, distribution and testing sequences of CDx and CGP, and associated genomic testing costs per patient were evaluated. RESULTS: Proportions of CDx and CGP testing varied across nine cancer types. Most patients underwent CDx testing once or twice, although some cohorts, particularly with non-small cell lung cancer (NSCLC), were tested thrice or more. Biliary tract cancer demonstrated the highest proportions for CGP testing alone, and both CDx and CGP testing. For both CDx and CGP testing, the greatest median costs were observed for ovarian and breast cancers, with bimodal peaks near US dollars (USD) 4000 and USD 5000. Median CDx costs were equal to or higher for patients who underwent both CDx and CGP testing compared with those who had CDx testing alone, particularly in breast, pancreatic, prostate, and ovarian cancers. For CDx testing alone, NSCLC, ovarian cancer, and prostate cancer had the highest costs, with a small peak near USD 1333. These results were mostly consistent across databases. CONCLUSIONS: Multiple CDx testing followed by CGP testing increased genomic testing costs per patient. Early implementation of CGP testing could reduce redundant testing and associated delays in treatment, thereby contributing to lower overall healthcare costs and more efficient treatment selection amid rapid advances in targeted therapies.

Administrative claims database↗

PubMed2026

Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer after Progression on First-line Osimertinib: Phase II ORCHARD Study.

PURPOSE: Osimertinib is the standard of care for first-line treatment for epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment. PATIENTS AND METHODS: ORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFRm NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile after progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a prespecified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS data was also assessed. RESULTS: This study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histogenomic landscape after first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 86% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed. CONCLUSIONS: This comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes. See related commentary by Gupta et al., p. 3718.

Humans↗

PubMed2026

Cross-Platform Concordance in DNA Methylation Based Classification of CNS Tumors.

DNA methylation profiling enables precise classification of pediatric central nervous system (CNS) tumors. Oxford Nanopore Technologies (ONT) offers same-day, single-sample methylation readouts, but its concordance with Illumina EPIC arrays in routine diagnostic tasks remains incompletely defined. We profiled 23 pediatric tumors (18 CNS, 5 non-CNS) by EPIC arrays and ONT. Methylation profiles from both platforms were classified with crossNN (brain model or pan-cancer model); ONT data were additionally classified with Rapid-CNS2 and Sturgeon. We compared (i) classifier agreement with integrated histology (w/o NGS) at family/class levels, (ii) pass-rate above platform-specific score cutoffs, (iii) cross-platform concordance of copy-number variation (CNV), and MGMT promoter methylation status. In CNS cases, ONT and EPIC methylation profiles demonstrated strong correlation, except for a single outlier (P2), which was excluded from further analysis. Comparative assessment of the two platforms showed that: (a) Molecular classification of CNS tumors using the crossNN classifier was consistent with histology (w/o NGS) at the family level in all cases. (b) Copy-number profiles showed high concordance between platforms. (c) MGMT promoter methylation status matched in 94% of cases (16/17). When comparing ONT-specific analysis pipelines using the ONT data, the Rapid-CNS2 pipeline yielded the most reliable class level assignments with 94% (16/17) concordance with the histopathological diagnosis, which marginally exceeded the crossNN and sturgeon classifiers. In non-CNS tumors, the pan-cancer model produced low-confidence outputs with poor agreement with histology (w/o NGS) (only 1/5 concordant), indicating limited readiness for these entities. In conclusion, ONT enables same-day, clinically reliable family-level CNS tumor classification with high concordance to arrays, while EPIC retains a modest class-level edge. A key limitation of ONT is its reliance on fresh-frozen DNA and on classifiers originally built around array-derived CpG sites, rather than on models developed natively from ONT data.

DNA methylation↗

PubMed1978

Application of a microchemical technique to the elucidation of enzyme activity profiles within single human mammary tumors.

An ultramicrochemical technique has been adapted to the evolution of enzyme profiles within individual human mammary tumors. Tandem observation of adjacent stained and lyophilized sections permitted dissection of microgram quantities of freeze-dried material within confirmed regions of malignancy. Enzymes frequently monitored to examine glycolytic, respiratory, and metastatic capacity were microanalyzed successfully: lactic dehydrogenase (LDH), phosphoglucose isomerase (PGI), malate dehydrogenase (MDH), acid phosphatase (AP), aldolase (ALD), glucose-6-phosphate dehydrogenase (G6PDH), pyruvate kinase (PK), alpha-glycerophosphate dehydrogenase (alpha-GOPDH), hexokinase (HK), and phosphofructokinase (PRK). All enzyme activities were higher in infiltrating ductal carcinomas than in fibroadenomas. Extracts of tumor cells mixed in varying proportions with brain or muscle extracts of rat evidenced no modification of expected activity. The technical adaptation described provided a sensitive methodology to resolve problems of relication, profile analysis, sample quantity, and selectivity within heterogeneous tissues.

Acid Phosphatase↗

PubMed2026

Somatic-only SDHD variant with tumor-specific loss of heterozygosity in metastatic carotid body tumor: a case report with review of literature.

Carotid body tumors (CBTs) are rare paragangliomas in which genetic predisposition, particularly pathogenic variants in succinate dehydrogenase (SDHx) genes, plays an important role in tumorigenesis. Previous genetic studies of CBTs have primarily focused on germline SDHx variants, whereas somatic alterations remain poorly characterized. Among SDHx genes, SDHB variants are known to be associated with a higher metastatic risk, while SDHD variants are generally linked to a lower metastatic rate. We report the case of a 41-year-old man who presented with a painless right-sided neck mass. Imaging studies demonstrated a hypervascular tumor located at the carotid bifurcation with circumferential encasement of the carotid artery. During surgery, the tumor was classified as a Shamblin type III CBT, and complete surgical resection with vascular reconstruction was performed. Histopathological examination confirmed paraganglioma with metastasis to a single cervical lymph node. Germline genetic testing did not reveal any pathogenic variants. However, comprehensive tumor genomic profiling identified a somatic SDHD c.304C>G (p.His102Asp) variant accompanied by tumor-specific loss of heterozygosity (LOH) and copy-number loss at the SDHD locus, findings compatible with biallelic SDHD inactivation. The patient remained free of recurrence during follow-up. To our knowledge, this represents the first reported case of metastatic CBT harboring a somatic-only SDHD variant with tumor-specific LOH. This case suggests that reliance on germline testing alone may underestimate the molecular drivers of CBT and highlights the potential clinical value of tumor-based genomic profiling for risk stratification and prognostic assessment.

Carotid body tumor↗

PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗

PubMed2025

Multimodal CustOmics: A unified and interpretable multi-task deep learning framework for multimodal integrative data analysis in oncology.

Characterizing cancer presents a delicate challenge as it involves deciphering complex biological interactions within the tumor's microenvironment. Clinical trials often provide histology images and molecular profiling of tumors, which can help understand these interactions. Despite recent advances in representing multimodal data for weakly supervised tasks in the medical domain, achieving a coherent and interpretable fusion of whole slide images and multi-omics data is still a challenge. Each modality operates at distinct biological levels, introducing substantial correlations between and within data sources. In response to these challenges, we propose a novel deep-learning-based approach designed to represent multi-omics & histopathology data for precision medicine in a readily interpretable manner. While our approach demonstrates superior performance compared to state-of-the-art methods across multiple test cases, it also deals with incomplete and missing data in a robust manner. It extracts various scores characterizing the activity of each modality and their interactions at the pathway and gene levels. The strength of our method lies in its capacity to unravel pathway activation through multimodal relationships and to extend enrichment analysis to spatial data for supervised tasks. We showcase its predictive capacity and interpretation scores by extensively exploring multiple TCGA datasets and validation cohorts. The method opens new perspectives in understanding the complex relationships between multimodal pathological genomic data in different cancer types and is publicly available on Github.

Deep Learning↗