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At least 19 recordsLinked to original sources
PubMed2026

HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.

Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS-driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly12 (G12X) or Gly13 (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln61 (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in NRAS-mutated malignancies.

Humans↗
PubMed1990

Detection of preferential NRAS mutations in human male germ cell tumors by the polymerase chain reaction.

We have studied 31 male germ cell tumors (GCTs) for probable mutations in codons 12, 13, and 61 of HRAS, KRAS, and NRAS oncogenes using the polymerase chain reaction. Twenty of the thirty-one tumors exhibited NRAS gene mutations, 14 in codon 61, and six in codon 12, whereas no mutations were detected in HRAS and KRAS genes. The NRAS mutations were equally prevalent in seminomatous and nonseminomatous GCTs. Thus 13 of 22 seminomas, six of seven embryonal carcinomas, and one of two mixed tumors exhibited mutations. Two non-seminomatous tumors (an embryonal carcinoma and a yolk sac/teratoma) had mutations in both codons 12 and 61. The high frequency of NRAS mutations observed in the present study suggests that NRAS gene products may play an important role in growth regulatory functions of premalignant and malignant germ cells.

DNA Mutational Analysis↗
PubMed2026

Histopathologic, Genomic, and Clinical Characteristics of Primary Cutaneous Melanocytic Tumors With Concomitant NRAS Q61 and IDH1 R132C Mutations.

Cutaneous melanocytic tumors with concomitant NRAS Q61 and IDH1 R132C mutations have been described as intermediate-grade melanocytomas with characteristic biphasic morphology, but the malignant end of this genotype-defined spectrum remains poorly characterized. We assessed histopathologic, immunohistochemical, molecular, and clinical features of 16 primary cutaneous melanocytic tumors harboring both mutations. Following integrated review, 7 tumors were classified as melanocytoma and 9 as melanoma. Melanocytomas showed reproducible biphasic architecture with congenital nevus-like features, a biphasic HMB-45 pattern, low Ki-67, PRAME negativity, retained p16, and minimal copy number variations (CNVs). Melanomas retained partial morphologic overlap in a subset but were distinguished by higher-grade cytology, immunohistochemical features supportive of malignancy, and progression-associated genomic alterations, including TERT promoter mutation (9/9), 9p21/CDKN2A loss (4/7), and higher CNV burden. NRAS and IDH1 variant allele frequencies were strongly concordant (r = 0.83, P < 0.001), supporting their presence in the same dominant clone. Clinically, two patients presented with stage IIIB disease, but no distant metastasis or melanoma-related death occurred during a median melanoma follow-up of 3.9 years (IQR, 2.5-5.1). In exploratory analyses, moderate-to-severe atypia (RR, 6.2; 95% CI, 1.0-38.8; P = .009), Ki-67 &#x2265;10% (RR, 4.4; 95% CI, 1.1-18.4; P = .003), lymphocytic infiltrate (RR, 2.4; 95% CI, 1.1-5.3; P = .03), absence of the typical biphasic pattern (RR, 2.4; 95% CI, 1.1-5.3; P = .03), and complete p16 loss (RR, 2.4; 95% CI, 1.1-5.3; P = .03) were associated with molecular or clinical progression to melanoma, defined as the presence of at least one of the following: TERT promoter mutation, pathogenic CDKN2A mutation, 9p21/CDKN2A loss, &#x2265;3 genome-wide segmental CNVs, or any metastasis. These findings support the existence of NRAS/IDH1 co-mutated melanoma as the malignant counterpart of NRAS/IDH1-mutated melanocytoma within a single genotype-defined spectrum.

IDH1 mutations↗
PubMed2025

In-depth assessment of BRAF, NRAS, KRAS, EGFR, and PIK3CA mutations on cell-free DNA in the blood of melanoma patients receiving immune checkpoint inhibition.

INTRODUCTION: Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI. METHODS: We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay's sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival. RESULTS: At baseline, ctDNA was detected in 64.5% of patients. Common mutations included BRAFV600E (43.8%) and NRASG12D (36.4%), followed by KRAS, EGFR, and PIK3CA variants. Overall tissue-plasma concordance was 51.6%, with more extended biopsy-plasma intervals associated with discordance (p&#x2009;=&#x2009;0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, p&#x2009;=&#x2009;0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3&#xa0;months) or those converting to positive (median 7.5&#xa0;months; p&#x2009;=&#x2009;0.0073). Early NRAS and KRAS ctDNA levels strongly predicted poor response (p&#x2009;=&#x2009;0.0069 and p&#x2009;=&#x2009;0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5-10 MM/mL) carried adverse prognostic implications (p&#x2009;=&#x2009;0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (p&#x2009;=&#x2009;0.047). Organ-specific mutation enrichment (e.g., KRASG12D in brain, EGFRG719A in lymph nodes) suggested possible metastatic tropism. CONCLUSION: Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.

Humans↗
PubMed1990

Hydrolysis of GTP by p21NRAS, the NRAS protooncogene product, is accompanied by a conformational change in the wild-type protein: use of a single fluorescent probe at the catalytic site.

2'(3')-O-(N-Methyl)anthraniloylguanosine 5'-triphosphate (mantGTP) is a fluorescent analogue of GTP that has similar properties to the physiological substrate in terms of its binding constant and the kinetics of its interactions with p21NRAS, the NRAS protooncogene product. There is a 3-fold increase in fluorescence intensity when mantGTP binds to p21NRAS. The rate constant for the cleavage of mantGTP complexed with the protein is similar to that of GTP, and cleavage is accompanied by a fluorescence intensity change in the wild-type protein complex. A two-phase fluorescence change also occurs when the nonhydrolyzable analogue 2'(3')-O-(N-methyl)anthraniloylguanosine 5'-[beta, gamma-imido]triphosphate (mantp[NH]ppG) binds to wild-type p21NRAS. The second phase occurs at the same rate as the second phase observed after mantGTP binding. Thus this second phase is probably a conformation change of the p21NRAS nucleotiside triphosphate complex and that the change controls the rate of GTP hydrolysis on the protein. With a transforming mutant, [Asp12]-p21NRAS, there is no second phase of the fluorescence change after mantGTP or mantp[NH]ppG binding, even though mantGTP is hydrolyzed. This shows that an equivalent conformational change does not occur and thus the mutant may stay in a "GTP-like" conformation throughout the GTPase cycle. These results are discussed in terms of the proposed role of p21NRAS in signal transduction and the transforming properties of the mutant.

Binding Sites↗
PubMed2025

Ras-MAPK pathway in patients with lupus nephritis.

BACKGROUND: Pathogenic mutations in genes encoding components of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway cause RASopathy. Here, we describe five unrelated patients with SLE carrying mutations associated with RASopathy and investigate the activity of the Ras-MAPK pathway. METHODS: Pathogenic variants were identified by whole-exome/whole-genome sequencing. The activity of the Ras-MAPK pathway in peripheral blood mononuclear cells (PBMC) and kidneys was evaluated using RNA sequencing and datasets from the nephroseq database, respectively. RESULTS: Five (likely) pathogenic variants in four Ras-MAPK genes were identified, including NRAS: c.G38A: p.G13D; ARAF: c.C1435T: p.R479C; KRAS: c.T341C: p.V114A; PTPN11: c.G455A: p.R152H and NRAS: c.G34A: p.G12S. Kidney injury is the main feature, presenting with nephrotic syndrome (2/5), proteinuria and haematuria (2/5). Acute kidney injury and rapidly progressive nephritic syndrome were noted in one patient each. Other clinical features included mucocutaneous lesions (5/5), cardiac involvement (4/5) and arthralgia (3/5). Laboratory abnormalities included hypocomplementaemia (5/5), presence of antiphospholipid antibodies (4/5), decreased regulatory T cells (3/3), pancytopenia (3/5) and persistent monocytosis (2/5). Kidney biopsy revealed lupus nephritis. Most patients responded well to standard therapy, with the exception of the patient with the NRAS p.G13D mutation who died. The Ras-MAPK pathway was activated in both PBMC and kidney of patients with LN as indicated by increased expression of NRAS, KRAS, RIT1, MRAS, PPP1CB, SHOC2, SOS2 and MAP2K1, as well as decreased expression of negative regulators of the Ras-MAPK pathway, CBL, LZTR1 and NF1. CONCLUSION: Kidney involvement may be the main feature of the clinical spectrum of RASopathy. Genetic screening should be considered for patients with early onset lupus.

Humans↗
PubMed1990

Restriction fragment length polymorphisms detected in N-ras-related sequences of rats and their linkage analyses.

Novel restriction fragment length polymorphisms (RFLPs) in inbred rats were revealed with the human N-ras gene as probe. Three fragments hybridizing to the probe were detected by Southern blot hybridization under highly stringent conditions, and one of the fragments showed variation in inbred rat strains. Furthermore, on hybridization under low-stringency conditions, an additional fragment hybridizing to the probe was observed, and this fragment also showed interstrain variation. These two variant fragments showed different distributions in 27 inbred rat strains and segregated in backcross progeny as codominant alleles of independent single autosomal loci. Therefore, the loci for these RFLPs were named Nras-1 and Nras-2, respectively. Analyses of linkages between the RFLPs and 11 other loci revealed that the Nras-2 locus was closely linked to the c locus (3.7 +/- 2.6%), which belongs to rat linkage group I.

Animals↗
PubMed2025

High Prevalence of Potential Molecular Therapeutic Targets in Poorly Differentiated Thyroid Carcinoma.

Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid cancer with aggressive clinical course and peculiar clinical/pathological characteristics but lacking effective therapeutic options, when surgery is not curative. We aimed at the molecular characterization of PDTC with a specific focus on the identification of potential therapeutic targets. A series of PDTC cases was selected from a multi-institutional network. Fifty-nine samples underwent wide targeted DNA and RNA next-generation sequencing (NGS) testing and immunohistochemical analysis for mismatch repair (MMR) proteins. Gene fusion analysis was enriched by 25 additional samples. Prevalence of MMR protein loss was 11.9%. The most prevalent mutations were in NRAS (25%) and TP53 (25%), mutually exclusive. TERT promoter (TERTp) mutations were detected in 19.6% of cases (10/51). NRAS-mutated cases were enriched for mutations in genes belonging to the same pathway. TP53-mutated samples lacked TERTp co-mutations, but were associated with mutations in PTEN and in genes related to MMR system and/or loss of MMR proteins. TERTp mutations were the most prevalent alterations (28%, 7/25) in a third group that lacked NRAS or TP53 mutations. Four cases harbored gene fusions, including two cases harboring the TBL1XR1::PIK3CA fusion that has never been reported in thyroid cancer, so far. In conclusion, PDTC may be genomically segregated in subgroups with specific molecular characteristics. Overall, targetable gene fusions have a prevalence of 9% (4/42). Moreover, 47% of cases are potential candidates for individualized target therapies since they harbor mutations in genes coding for potentially targetable molecules and/or have defects in the MMR system.

Humans↗
PubMed1991

Effect of ras-gene transformation on the inhibition of NIH3T3 cell growth by pertussis toxin.

To investigate the relationship between the effects of a pertussis toxin-inhibitable class of G-proteins and the ras family of protooncogenes on cell growth, we isolated multiple cell lines transformed by oncogenic Hras or Nras genes and measured the ability of pertussis toxin to inhibit their growth rate. Although all of the cell lines were morphologically transformed and could grow in agar suspension, there was considerable variability in their resistance to pertussis toxin, ranging from cell lines completely resistant to pertussis toxin to cell lines as sensitive to pertussis toxin as the parental cells from which they derived. For those lines resistant to pertussis toxin, this resistance is not due to an inability of pertussis toxin to reach or react with its intracellular target; pertussis toxin could be shown to ADP-ribosylate the endogenous G-proteins of all lines tested regardless of whether it affected their growth rate. There was a strong correlation between the level of active ras protein expressed in the different lines and the degree of resistance to pertussis toxin (r = 0.80). Although the Hras-transformed cell lines were more resistant to pertussis toxin as a group than the Nras-transformed cell lines, we believe that this is not a primary difference between Nras and Hras, but, rather, is due to a higher average level of expression of ras in the cell lines receiving Hras. We suggest that the consequences of ras transformation vary with the concentration of oncogenic ras present in the cell, and that different assays or different properties of transformation show different sensitivities to the level of ras expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate Ribose↗
PubMed2026

Anatomical location defines distinct molecular subtypes of mucosal melanoma.

BACKGROUND: Mucosal melanoma (MM) is a rare and aggressive melanoma subtype that is understudied. The relationships between anatomical location, genomic alterations, stage at presentation, and survival remain incompletely characterized. METHODS: We carried out a retrospective single tertiary center study of 105 patients with histologically confirmed MM diagnosed between 1996 and 2025. Clinical and genomic data were analyzed to evaluate associations between anatomical location, mutational profile, stage at presentation, and survival outcomes, including melanoma-specific mortality. RESULTS: Lower-body tumors arising in the anus or genital areas were enriched for KIT and splicing factor 3 subunit B1 alterations, whereas NRAS mutations were distributed across anatomical regions. Among the two most common mutated genes, NRAS-mutant tumors were more likely than KIT-mutant tumors to present with metastatic disease [53% versus 19%; P = 0.046, odds ratio (OR) 4.7, 95% confidence interval (CI) 1.15-19.41]. Lower-body tumors were associated with worse overall survival (OS) than upper-body tumors (median 2.81 versus 8.40 years; OR = 0.05) and with higher melanoma-specific mortality. In multivariable analyses, upper-body location remained independently associated with improved OS (hazard ratio 0.14, 95% CI 0.05-0.36, P < 0.001). CONCLUSIONS: Anatomical location of MMs and genomic alterations define biologically and clinically distinct subtypes.

KIT mutation↗
PubMed2025

Biomarker identification through spatial proteomics for the characterization of indeterminate thyroid nodules.

PURPOSE: The identification of novel molecular biomarkers may assist in the characterization of indeterminate thyroid nodules, which pose significant diagnostic challenges. Here, we aimed to explore the potential of proteomic analyses to support biomarker discovery in challenging thyroid lesions. METHODS: Linear Discriminant Analysis (LDA) was applied to Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI-MSI) data from 44 thyroid neoplasms to select the most impactful molecular features for the classification of different tumor histologies, as well as for the distinction between NRAS-mutant (mNRAS) and NRAS-wild-type (wtNRAS) tumors. Relevant peaks were subsequently identified through nanoscale liquid chromatography electrospray ionization tandem mass spectrometry (nLC-ESI-MS/MS). RESULTS: The LDA selected nine relevant molecular markers distinguishing noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs) from other tumor histologies (balanced accuracy = 73%), as well as 19 relevant markers able to identify mNRAS cases (balanced accuracy = 84%). Nine differentially expressed proteins were putatively identified: among them, ATP-dependent RNA helicase DDX42 showed a similar distribution between NIFTPs and papillary thyroid carcinomas (PTCs) / follicular variant PTCs (FVPTCs), while the distribution of the Histone H4 signal was similar between NIFTPs and follicular adenomas (FAs). In addition, Protein disulfide-isomerase A1 and Complement C4-B were overexpressed in wtNRAS compared to mNRAS cases, regardless of histology. CONCLUSION: The LDA-selected features enable to distinguish NIFTPs from morphologically similar lesions and to discriminate between mNRAS and wtNRAS cases. The identified markers might complement genetic analyses and provide insights into the distinct pathogenic drivers behind the development of mNRAS compared to wtNRAS lesions.

Humans↗
PubMed2026

Mutational Landscape and Clonal Dynamics in AML Undergoing PTCy Hematopoietic Cell Transplantation.

To improve risk stratification, we performed targeted NGS at diagnosis in 191 patients with AML undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. We also investigated clonal evolution using paired diagnostic and relapse samples from 39 individuals. A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in &#x223c;70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. Incorporating TP53 and WT1 into risk models, recognizing context-dependent effects of DNMT3A and RUNX1, and applying longitudinal genomic monitoring may help guide personalized strategies to prevent relapse. Extended abstract BACKGROUND Relapse remains the leading cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), yet the genetic mechanisms underlying post-transplant relapse remain poorly understood, particularly in the era of post-transplant cyclophosphamide (PTCy). Characterizing the mutational landscape at diagnosis and the clonal evolution leading to relapse may improve post-transplant risk stratification and identify opportunities for personalized surveillance and intervention. OBJECTIVES To characterize the diagnostic mutational landscape, evaluate its prognostic significance, and investigate clonal evolution from diagnosis to relapse in AML patients undergoing myeloablative HCT with PTCy-based graft-versus-host disease prophylaxis. STUDY DESIGN We performed targeted next-generation sequencing (NGS) at diagnosis in 191 consecutive AML patients undergoing myeloablative allogeneic HCT with PTCy-based prophylaxis. Paired diagnostic and relapse samples were available for 39 patients to evaluate clonal evolution. RESULTS A total of 610 mutations were detected in 184 patients (96%), most commonly in FLT3 (26%), DNMT3A (25%), RUNX1 (24%), and NPM1 (19%). Sixteen unique fusion genes were identified in 35 patients, with KMT2A (43%) and core binding factor rearrangements (23%) being the most frequent. TP53 and WT1 mutations were strongly associated with adverse outcomes, whereas NPM1 retained favorable significance. RUNX1 co-mutations with SF3B1 or NRAS were associated with inferior survival. In an exploratory allelic analysis, multi-hit TP53 alterations, but not single-hit mutations, were associated with distinctly poorer OS, EFS, and relapse risk. Relapse involved mutational shifts in &#x223c;70% of cases, with significant enrichment of WT1 and more modest increases in TP53, KRAS, ASXL1, NF1, and MECOM, while DNMT3A, TET2, and ASXL1 persisted stably. Neither acute nor chronic graft-versus-host disease was associated with molecular remodeling at relapse. CONCLUSIONS This study provides a comprehensive characterization of the mutational landscape and clonal evolution of AML undergoing contemporary PTCy-based allogeneic HCT. TP53 and WT1 identify patients at particularly high risk of post-transplant relapse, whereas NPM1 retains favorable prognostic significance. The frequent acquisition of new genetic lesions at relapse underscores the dynamic nature of post-transplant clonal evolution and supports longitudinal molecular monitoring together with genomically informed post-transplant surveillance and relapse-prevention strategies.

Clonal Dynamics↗
PubMed2026

Recurrent and unusual infections unmasking a rare inborn error of immunity: a case report RAS-associated Autoimmune Lymphoproliferative Disease (RALD).

BACKGROUND: RAS-associated Autoimmune Lymphoproliferative Disease (RALD) is a rare, non-malignant lymphoproliferative disorder caused by somatic mutations in RAS genes that impair lymphocyte apoptosis. Patients often present with features of lymphoproliferation, autoimmune manifestations, and an increased risk of malignant transformation. CASE PRESENTATION: We report the case of a 3-year-old boy with splenic microabscesses and Burkholderia pseudomallei IgM serology positivity, who was treated as melioidosis. He had recurrent respiratory infections and chronic rhinorrhoea since the age of one year. Clinical examination revealed persistent lymphadenopathy and hepatosplenomegaly. Laboratory investigations demonstrated persistent absolute monocytosis and thrombocytopenia, while immunological evaluation showed elevated IgM levels and B-cell lymphocytosis. Whole exome sequencing identified a heterozygous pathogenic variant in NRAS, NM_002524.5:c.35G&#x2009;>&#x2009;C, NP_002515.1:p.Gly12Ala, establishing the diagnosis of RALD. The patient was subsequently started on antibiotic prophylaxis and immunoglobulin replacement therapy, and his family was counseled regarding the potential role of immunosuppressive therapy and hematopoietic stem cell transplantation (HSCT) in future management. CONCLUSIONS: This case highlights the coexistence of an unusual infection with a rare inborn error of immunity, expanding the recognized infectious spectrum of RALD. It underscores the importance of considering RALD in patients presenting with recurrent or atypical infections and persistent lymphoproliferative features. Early recognition and molecular genetic testing are essential for confirming the diagnosis and guiding individualized management.

Humans↗
PubMed2026

DNA Methylation Profiling of Pediatric Ectomesenchymoma Supports Embryonal Rhabdomyosarcoma-Like Epigenetic Identity.

Ectomesenchymoma is a rare, biphenotypic pediatric tumor combining rhabdomyoblastic and neuroectodermal differentiation. We characterize two novel cases through integrated genomics and the first report of genome-wide DNA methylation profiling. Both tumors harbored RAS-pathway mutations (HRAS p.Gly13Arg; NRAS p.Gln61His). Methylation analysis, including microdissected components, consistently aligned ectomesenchymoma with the embryonal rhabdomyosarcoma superfamily, revealing a shared myogenic epigenetic program despite neural differentiation. Shared copy-number profiles across distinct histological regions supported a monoclonal origin. Overall, our data support a close biological relationship between ectomesenchymoma and embryonal rhabdomyosarcoma and indicate that RAS-pathway testing and methylation profiling can significantly refine diagnostic precision.

Humans↗
PubMed2026

Genomic Characterization of ETV6::RUNX1-Positive Childhood B-ALL in a Chinese Cohort: Novel Fusion Partners, Co-Occurring Mutations, and Risk-Stratifying Biomarkers.

BACKGROUND: ETV6::RUNX1 is the most common genetic abnormality in pediatric B-cell acute lymphoblastic leukemia (ALL; &#x223c;25%), yet the comprehensive genetic architecture and molecular predictors of intermediate-risk (IR) stratification remain incompletely characterized. METHODS: We performed whole-transcriptome sequencing (Illumina NovaSeq 6000, rRNA depletion, 41.70 Gb/sample) on bone marrow samples from 93 pediatric ETV6::RUNX1-positive B-ALL patients. Bioinformatics analysis included STAR alignment, MuTect2 variant calling, FusionCatcher fusion detection, and VEP annotation. The Jaccard index with permutation testing assessed mutation co-occurrence; logistic regression identified independent predictors of IR classification. RESULTS: Beyond ETV6::RUNX1, we identified 51 distinct fusion genes across the cohort, including the reciprocal RUNX1-ETV6 (73.1%), chr8::KLF1210 (38.7%), and KLF12-chr8 (34.4%). Somatic mutations in 249 genes were detected; the most frequent were KIAA1715 (17.2%), KRAS (11.8%), and NSD2 (10.8%). Network analysis revealed significant chromatin modifier co-occurrence (KIAA1715-KMT2C: J = 0.136, p = 0.015) and KRAS-NRAS mutual exclusivity (J = 0.000, p = 0.042). PTCH1 (OR = 3.50, 95% CI 0.21-58.49, p = 0.41) and GNB1 (OR = 6.5, 95% CI 1.2-34.8, p = 0.029) mutations independently predicted IR classification. chr8::KLF1210 fusion correlated with higher Day-19 MRD levels (p = 0.038). CONCLUSIONS: GNB1 mutation represents a novel independent predictor of IR stratification in ETV6::RUNX1-positive B-ALL. The chromatin modifier co-occurrence module and extensive fusion architecture reveal biological heterogeneity within this favorable-risk subtype, with potential implications for risk-adapted therapeutic strategies.

B&#x2010;ALL↗
PubMed1990

Frequent rearrangement of chromosomal bands 1p22 and 11q13 in squamous cell carcinomas of the head and neck.

We report the finding of clonal structural chromosome abnormalities in short-term cultures from 15 squamous cell carcinomas of the head and neck region. When the distribution of chromosomal breakpoints in these 15 tumors and in the 16 head and neck carcinomas previously described are assessed, a marked clustering is seen at bands 1p22 and 11q13, which are rearranged in eight and nine tumors, respectively. No other band was involved in aberrations in more than five tumors. Cytogenetic evidence of gene amplification was seen in four tumors, three times in the form of homogeneously staining regions (twice located in 11q13), and in one tumor as double minutes. Among the candidate genes for such amplification are BCLI, INT2, and HSTI, all of which map to 11q13, and NRAS, which maps to 1p22. All these oncogenes have previously been shown to be amplified in subsets of head and neck carcinomas. We conclude that bands 1p22 and 11q13 are nonrandomly involved in chromosomal rearrangements in head and neck carcinomas and suggest that activation of oncogenes located in these bands may proceed via cytogenetic mechanisms.

Aged↗