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High-Grade Uterine Sarcoma: First Report of a MEIS2::FOXO4 Fusion
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-04-18 DOI: 10.1002/gcc.70043
Gulisa Turashvili, Edwin Choy, Adam S. Fisch, Esther Oliva

Uterine sarcomas are uncommon mesenchymal neoplasms ranging from low- to high-grade or undifferentiated. High-grade sarcomas are characterized by various morphologic, immunohistochemical, and molecular alterations. Here, we report the first description of a patient with uterine sarcoma with a MEIS2::FOXO4 fusion. This tumor showed alternating fascicular and diffuse architecture with a prominent nodular growth displaying striking hyalinization and less prominent myxoid background admixed with more cellular internodular areas. The neoplastic cells ranged from spindled to stellate to epithelioid and exhibited variable cytologic atypia and mitotic activity. Immunohistochemical stains showed diffuse expression of smooth muscle actin, preserved expression of PTEN, ATRX, and Rb1, wild-type expression of p53, weak expression of PLAG1, multifocal expression of MDM2, and no reactivity for desmin. RNA sequencing detected a MEIS2::FOXO4 gene fusion with breakpoints at MEIS2 exon 6 and FOXO4 exon 2. Although this gene fusion has been described in other soft tissue neoplasms, it has not been previously reported in uterine sarcomas and highlights the significance of performing molecular analysis in uterine mesenchymal tumors with unusual morphology and/or immunophenotype.

{"title":"High-Grade Uterine Sarcoma: First Report of a MEIS2::FOXO4 Fusion","authors":"Gulisa Turashvili,&nbsp;Edwin Choy,&nbsp;Adam S. Fisch,&nbsp;Esther Oliva","doi":"10.1002/gcc.70043","DOIUrl":"https://doi.org/10.1002/gcc.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>Uterine sarcomas are uncommon mesenchymal neoplasms ranging from low- to high-grade or undifferentiated. High-grade sarcomas are characterized by various morphologic, immunohistochemical, and molecular alterations. Here, we report the first description of a patient with uterine sarcoma with a <i>MEIS2::FOXO4</i> fusion. This tumor showed alternating fascicular and diffuse architecture with a prominent nodular growth displaying striking hyalinization and less prominent myxoid background admixed with more cellular internodular areas. The neoplastic cells ranged from spindled to stellate to epithelioid and exhibited variable cytologic atypia and mitotic activity. Immunohistochemical stains showed diffuse expression of smooth muscle actin, preserved expression of PTEN, ATRX, and Rb1, wild-type expression of p53, weak expression of PLAG1, multifocal expression of MDM2, and no reactivity for desmin. RNA sequencing detected a <i>MEIS2::FOXO4</i> gene fusion with breakpoints at <i>MEIS2</i> exon 6 and <i>FOXO4</i> exon 2. Although this gene fusion has been described in other soft tissue neoplasms, it has not been previously reported in uterine sarcomas and highlights the significance of performing molecular analysis in uterine mesenchymal tumors with unusual morphology and/or immunophenotype.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
NR1D1::MAML3 Fusion in an Aggressive Mesenchymal Neoplasm
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-04-18 DOI: 10.1002/gcc.70049
Minh Chau Ta, Camille Gandon, Maxence Mancini, Philippe Lantier, Olaf Mercier, Samia Mourah, Maxime Battistella

NR1D1-rearranged tumors are distinct mesenchymal neoplasms with epithelioid morphology and aggressive potential. This report presents an 85-year-old male with a slow-growing sternal mass identified as a pseudo-cyst, characterized by a dense proliferation of epithelioid tumor cells. These cells exhibited pale cytoplasm and uniform oval nuclei, with some areas of spindle cells and extensive necrosis. The mitotic count was 12 per 1.7 mm2. Immunohistochemical analysis showed positivity for EMA, ERG, AE1AE3, and CK7, but negativity for SMA, desmin, CD117, CD31, SOX10, MelanA, synaptophysin, INSM1, CK20, CD34, TTF1, WT1, caldesmon, myogenin, and collagen IV. INI1 expression was preserved. The Ki67 index was high. Whole-transcriptome sequencing revealed an in-frame NR1D1::MAML3 fusion, retaining two key protein domains of NR1D1. Nine months post-diagnosis, the patient developed pleural, bilateral lung, and bone metastases. This case underscores the necessity of molecular analysis for precise tumor classification, given the tumor's varied morphological features and poor prognosis.

{"title":"NR1D1::MAML3 Fusion in an Aggressive Mesenchymal Neoplasm","authors":"Minh Chau Ta,&nbsp;Camille Gandon,&nbsp;Maxence Mancini,&nbsp;Philippe Lantier,&nbsp;Olaf Mercier,&nbsp;Samia Mourah,&nbsp;Maxime Battistella","doi":"10.1002/gcc.70049","DOIUrl":"https://doi.org/10.1002/gcc.70049","url":null,"abstract":"<div>\u0000 \u0000 <p><i>NR1D1</i>-rearranged tumors are distinct mesenchymal neoplasms with epithelioid morphology and aggressive potential. This report presents an 85-year-old male with a slow-growing sternal mass identified as a pseudo-cyst, characterized by a dense proliferation of epithelioid tumor cells. These cells exhibited pale cytoplasm and uniform oval nuclei, with some areas of spindle cells and extensive necrosis. The mitotic count was 12 per 1.7 mm<sup>2</sup>. Immunohistochemical analysis showed positivity for EMA, ERG, AE1AE3, and CK7, but negativity for SMA, desmin, CD117, CD31, SOX10, MelanA, synaptophysin, INSM1, CK20, CD34, TTF1, WT1, caldesmon, myogenin, and collagen IV. INI1 expression was preserved. The Ki67 index was high. Whole-transcriptome sequencing revealed an in-frame <i>NR1D1</i>::<i>MAML3</i> fusion, retaining two key protein domains of <i>NR1D1</i>. Nine months post-diagnosis, the patient developed pleural, bilateral lung, and bone metastases. This case underscores the necessity of molecular analysis for precise tumor classification, given the tumor's varied morphological features and poor prognosis.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143845914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
EWSR1::SSX1 Fusion-Driven Synovial Sarcoma: A Case Presentation and Review of the Literature
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-04-10 DOI: 10.1002/gcc.70048
Jesus Vega-Gonzalez, Jose Antonio Cortés Toro, Esthefanía Latorre García, Gloria Marquina Ospina, Montserrat de la Torre Serrano, Ana María Colino Gallardo, Reyes Bergillos Giménez, Desiré Hernández Martínez, Alejandro García Egido, Lorenzo Alarcón García, Lone Nielsen, Jose Carlos Plaza, Luis Ortega Medina

According to the 5th edition of the WHO Classification of Soft Tissue and Bone Tumors, the diagnosis of synovial sarcoma relies on morphology, immunohistochemistry, and the detection of a specific fusion involving the SS18 gene with a member of the SSX gene family. However, few cases of synovial sarcoma that do not harbor such molecular alterations have been recently reported. We present the case of a patient with a diffuse pleural mass and pleural effusion that showed in a core needle biopsy a spindle cell neoplasia morphologically suggestive of synovial sarcoma. An SS18 break-apart FISH was performed with a negative result. Afterwards, an EWSR1::SSX1 fusion was detected by next-generation sequencing. There is scarce literature on non-SS18 fusion-driven synovial sarcomas, and no study has evaluated whether these novel molecular alterations have a relevant clinical impact on patients beyond the diagnostic value.

{"title":"EWSR1::SSX1 Fusion-Driven Synovial Sarcoma: A Case Presentation and Review of the Literature","authors":"Jesus Vega-Gonzalez,&nbsp;Jose Antonio Cortés Toro,&nbsp;Esthefanía Latorre García,&nbsp;Gloria Marquina Ospina,&nbsp;Montserrat de la Torre Serrano,&nbsp;Ana María Colino Gallardo,&nbsp;Reyes Bergillos Giménez,&nbsp;Desiré Hernández Martínez,&nbsp;Alejandro García Egido,&nbsp;Lorenzo Alarcón García,&nbsp;Lone Nielsen,&nbsp;Jose Carlos Plaza,&nbsp;Luis Ortega Medina","doi":"10.1002/gcc.70048","DOIUrl":"https://doi.org/10.1002/gcc.70048","url":null,"abstract":"<div>\u0000 \u0000 <p>According to the 5th edition of the WHO Classification of Soft Tissue and Bone Tumors, the diagnosis of synovial sarcoma relies on morphology, immunohistochemistry, and the detection of a specific fusion involving the <i>SS18</i> gene with a member of the <i>SSX</i> gene family. However, few cases of synovial sarcoma that do not harbor such molecular alterations have been recently reported. We present the case of a patient with a diffuse pleural mass and pleural effusion that showed in a core needle biopsy a spindle cell neoplasia morphologically suggestive of synovial sarcoma. An <i>SS18</i> break-apart FISH was performed with a negative result. Afterwards, an <i>EWSR1::SSX1</i> fusion was detected by next-generation sequencing. There is scarce literature on non-SS18 fusion-driven synovial sarcomas, and no study has evaluated whether these novel molecular alterations have a relevant clinical impact on patients beyond the diagnostic value.</p>\u0000 </div>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Subtyping Burkitt Lymphoma by DNA Methylation
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-04-07 DOI: 10.1002/gcc.70042
Selina Glaser, Rabea Wagener, Helene Kretzmer, Cristina López, Maria Joao Baptista, Susanne Bens, Stephan Bernhart, Kishor Bhatia, Arndt Borkhardt, Shaymaa Elgaafary, Steve Hoffmann, Daniel Hübschmann, Michael Hummel, Wolfram Klapper, Julia Kolarova, Markus Kreuz, Stefano Lazzi, Markus Löffler, Jose Tomas Navarro, Janet Neequaye, Noel Onyango, Timothy Onyuma, German Ott, Bernhard Radlwimmer, Marius Rohde, Andreas Rosenwald, Maciej Rosolowski, Matthias Schlesner, Monika Szczepanowski, Gustavo Tapia, Wilhelm Wößmann, Ralf Küppers, Lorenz Trümper, Lorenzo Leoncini, Peter Lichter, Coral del Val, Ole Ammerpohl, Birgit Burkhardt, Sam M. Mbulaiteye, Reiner Siebert, ICGC MMML-Seq Consortium; MMML Project

Burkitt lymphoma (BL) is an aggressive germinal center B-cell-derived malignancy. Historically, sporadic, endemic, and immunodeficiency-associated variants were distinguished, which differ in the frequency of Epstein–Barr virus (EBV) positivity. Aiming to identify subgroups based on DNA methylation patterns, we here profiled 96 BL cases, 17 BL cell lines, and six EBV-transformed lymphoblastoid cell lines using Illumina BeadChip arrays. DNA methylation analyses clustered the cases into four subgroups: two containing mostly EBV-positive cases (BL-mC1, BL-mC2) and two containing mostly EBV-negative cases (BL-mC3, BL-mC4). The subgroups BL-mC1/2, enriched for EBV-positive cases, showed increased DNA methylation, epigenetic age, and, in part, proliferation history compared to BL-mC3/4. CpGs hypermethylated in EBV-positive BLs were enriched for polycomb repressive complex 2 marks, while the CpGs hypomethylated in EBV-negative BLs were linked to, for example, B-cell receptor signaling. EBV-associated hypermethylation affected regulatory regions of genes frequently mutated in BL (e.g., CCND3, TP53) and impacted superenhancers. This finding suggests that hypermethylation may compensate for the lower mutational burden of pathogenic drivers in EBV-positive BLs. Though minor, significant differences were also observed between EBV-positive endemic and sporadic cases (e.g., at the SOX11 and RUNX1 loci). Our findings suggest that EBV status, rather than epidemiological variants, drives the DNA methylation-based subgrouping of BL.

{"title":"Subtyping Burkitt Lymphoma by DNA Methylation","authors":"Selina Glaser,&nbsp;Rabea Wagener,&nbsp;Helene Kretzmer,&nbsp;Cristina López,&nbsp;Maria Joao Baptista,&nbsp;Susanne Bens,&nbsp;Stephan Bernhart,&nbsp;Kishor Bhatia,&nbsp;Arndt Borkhardt,&nbsp;Shaymaa Elgaafary,&nbsp;Steve Hoffmann,&nbsp;Daniel Hübschmann,&nbsp;Michael Hummel,&nbsp;Wolfram Klapper,&nbsp;Julia Kolarova,&nbsp;Markus Kreuz,&nbsp;Stefano Lazzi,&nbsp;Markus Löffler,&nbsp;Jose Tomas Navarro,&nbsp;Janet Neequaye,&nbsp;Noel Onyango,&nbsp;Timothy Onyuma,&nbsp;German Ott,&nbsp;Bernhard Radlwimmer,&nbsp;Marius Rohde,&nbsp;Andreas Rosenwald,&nbsp;Maciej Rosolowski,&nbsp;Matthias Schlesner,&nbsp;Monika Szczepanowski,&nbsp;Gustavo Tapia,&nbsp;Wilhelm Wößmann,&nbsp;Ralf Küppers,&nbsp;Lorenz Trümper,&nbsp;Lorenzo Leoncini,&nbsp;Peter Lichter,&nbsp;Coral del Val,&nbsp;Ole Ammerpohl,&nbsp;Birgit Burkhardt,&nbsp;Sam M. Mbulaiteye,&nbsp;Reiner Siebert,&nbsp;ICGC MMML-Seq Consortium; MMML Project","doi":"10.1002/gcc.70042","DOIUrl":"https://doi.org/10.1002/gcc.70042","url":null,"abstract":"<p>Burkitt lymphoma (BL) is an aggressive germinal center B-cell-derived malignancy. Historically, sporadic, endemic, and immunodeficiency-associated variants were distinguished, which differ in the frequency of Epstein–Barr virus (EBV) positivity. Aiming to identify subgroups based on DNA methylation patterns, we here profiled 96 BL cases, 17 BL cell lines, and six EBV-transformed lymphoblastoid cell lines using Illumina BeadChip arrays. DNA methylation analyses clustered the cases into four subgroups: two containing mostly EBV-positive cases (BL-mC1, BL-mC2) and two containing mostly EBV-negative cases (BL-mC3, BL-mC4). The subgroups BL-mC1/2, enriched for EBV-positive cases, showed increased DNA methylation, epigenetic age, and, in part, proliferation history compared to BL-mC3/4. CpGs hypermethylated in EBV-positive BLs were enriched for polycomb repressive complex 2 marks, while the CpGs hypomethylated in EBV-negative BLs were linked to, for example, B-cell receptor signaling. EBV-associated hypermethylation affected regulatory regions of genes frequently mutated in BL (e.g., <i>CCND3</i>, <i>TP53</i>) and impacted superenhancers. This finding suggests that hypermethylation may compensate for the lower mutational burden of pathogenic drivers in EBV-positive BLs. Though minor, significant differences were also observed between EBV-positive endemic and sporadic cases (e.g., at the <i>SOX11</i> and <i>RUNX1</i> loci). Our findings suggest that EBV status, rather than epidemiological variants, drives the DNA methylation-based subgrouping of BL.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
EGFR-KDD Myofibroblastic Neoplasm or Congenital Peribronchial Myofibroblastic Tumor (CPMT)? Report of a Congenital Myofibroblastic Neoplasm With Unusual Histologic Features 表皮生长因子受体-KDD肌纤维母细胞瘤还是先天性支气管周围肌纤维母细胞瘤(CPMT)?一例具有异常组织学特征的先天性肌成纤维细胞肿瘤的报告
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-04-03 DOI: 10.1002/gcc.70032
Emma Rullo, Sabina Barresi, Sabrina Rossi, Sara Patrizi, Evelina Miele, Marta Barisella, Michela Casanova, Andrea Ferrari, Stefano Chiaravalli, Gloria Pelizzo, Rita Alaggio

EGFR-kinase-domain duplication (KDD) has been reported in Infantile fibrosarcoma-like myofibroblastic tumors and cellular mesoblastic nephroma. We report a pulmonary neoplasm with EGFR-(KDD) and infantile fibrosarcoma-like histologic features in a female infant with an unusual clinical and histologic evolution, characterized by persistent disease with morphologic features of Congenital Peribronchial Myofibroblastic Tumor (CPMT) after chemotherapy and targeted therapy. The CPMT morphology with EGFR-KDD in the post-therapy specimen might be an evolution induced by the treatment, which suggests the hypothesis that CPMT is part of the morphologic spectrum of infantile fibrosarcoma/cellular mesoblastic nephroma.

{"title":"EGFR-KDD Myofibroblastic Neoplasm or Congenital Peribronchial Myofibroblastic Tumor (CPMT)? Report of a Congenital Myofibroblastic Neoplasm With Unusual Histologic Features","authors":"Emma Rullo,&nbsp;Sabina Barresi,&nbsp;Sabrina Rossi,&nbsp;Sara Patrizi,&nbsp;Evelina Miele,&nbsp;Marta Barisella,&nbsp;Michela Casanova,&nbsp;Andrea Ferrari,&nbsp;Stefano Chiaravalli,&nbsp;Gloria Pelizzo,&nbsp;Rita Alaggio","doi":"10.1002/gcc.70032","DOIUrl":"https://doi.org/10.1002/gcc.70032","url":null,"abstract":"<p>EGFR-kinase-domain duplication (KDD) has been reported in Infantile fibrosarcoma-like myofibroblastic tumors and cellular mesoblastic nephroma. We report a pulmonary neoplasm with EGFR-(KDD) and infantile fibrosarcoma-like histologic features in a female infant with an unusual clinical and histologic evolution, characterized by persistent disease with morphologic features of Congenital Peribronchial Myofibroblastic Tumor (CPMT) after chemotherapy and targeted therapy. The CPMT morphology with <i>EGFR-KDD</i> in the post-therapy specimen might be an evolution induced by the treatment, which suggests the hypothesis that CPMT is part of the morphologic spectrum of infantile fibrosarcoma/cellular mesoblastic nephroma.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 4","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of Cis-Regulatory Mechanisms via Non-Coding Mutations in Acute Lymphoblastic Leukemia
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-03-27 DOI: 10.1002/gcc.70045
Efe Aydın, Eleanor L. Woodward, Gladys Telliam Dushime, Rebeqa Gunnarsson, Henrik Lilljebjörn, Larissa H. Moura-Castro, Thoas Fioretos, Bertil Johansson, Kajsa Paulsson, Minjun Yang

The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP-seq and ATAC-seq data, we found 128 non-coding hotspots associated with differentially expressed genes nearby, which were enriched for cis-regulatory elements, demonstrating the effectiveness of multi-omics integration in distinguishing pathogenic mutations from passengers. We identified one mutational hotspot that was associated with increased expression of the leukemia-associated gene NRAS in three primary ALLs. Micro-C analysis in the leukemia cell line demonstrated interactions between the hotspot region and NRAS regulatory elements. Dual luciferase assays indicated that the mutations disrupted regulatory interactions and CRISPR-mediated deletion of the region significantly upregulated NRAS, confirming the hypothesized regulatory link. Altogether, we provide new insights into the functional roles of non-coding mutations in leukemia.

{"title":"Discovery of Cis-Regulatory Mechanisms via Non-Coding Mutations in Acute Lymphoblastic Leukemia","authors":"Efe Aydın,&nbsp;Eleanor L. Woodward,&nbsp;Gladys Telliam Dushime,&nbsp;Rebeqa Gunnarsson,&nbsp;Henrik Lilljebjörn,&nbsp;Larissa H. Moura-Castro,&nbsp;Thoas Fioretos,&nbsp;Bertil Johansson,&nbsp;Kajsa Paulsson,&nbsp;Minjun Yang","doi":"10.1002/gcc.70045","DOIUrl":"https://doi.org/10.1002/gcc.70045","url":null,"abstract":"<p>The non-coding genome, constituting 98% of human DNA, remains largely unexplored, yet holds potential for identifying new biomarkers and therapeutic targets in acute lymphoblastic leukemia (ALL). In this study, we conducted a systematic analysis of recurrent somatic non-coding single nucleotide variants (SNVs) in pediatric B-cell precursor (BCP) ALL. We leveraged whole genome sequencing (WGS) data from 345 pediatric BCP ALL cases, representing all major genetic subtypes and identified 346 mutational hotspots that harbored somatic SNVs in at least three cases. Through the integration of paired RNA sequencing along with published ChIP-seq and ATAC-seq data, we found 128 non-coding hotspots associated with differentially expressed genes nearby, which were enriched for cis-regulatory elements, demonstrating the effectiveness of multi-omics integration in distinguishing pathogenic mutations from passengers. We identified one mutational hotspot that was associated with increased expression of the leukemia-associated gene <i>NRAS</i> in three primary ALLs. Micro-C analysis in the leukemia cell line demonstrated interactions between the hotspot region and <i>NRAS</i> regulatory elements. Dual luciferase assays indicated that the mutations disrupted regulatory interactions and CRISPR-mediated deletion of the region significantly upregulated <i>NRAS</i>, confirming the hypothesized regulatory link. Altogether, we provide new insights into the functional roles of non-coding mutations in leukemia.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genome-Wide DNA Methylation and Copy Number Alterations in Gastrointestinal Stromal Tumors
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-03-27 DOI: 10.1002/gcc.70046
Tony G. Kleijn, Baptiste Ameline, Roos F. Bleckman, Wierd Kooistra, Evert van den Broek, Gilles F. H. Diercks, Bettien M. van Hemel, Bert Timmer, Wim Timens, Gursah Kats-Ugurlu, Léon C. van Kempen, Boudewijn van Etten, Ed Schuuring, Albert J. H. Suurmeijer, Jacco J. de Haan, Daniel Baumhoer, Anna K. L. Reyners, Arjen H. G. Cleven

Gastrointestinal stromal tumors (GISTs) span a broad clinical spectrum, from indolent neoplasms to life-threatening metastatic tumors. A persistent limitation of current risk stratification systems is that a subset of GISTs is graded as low-risk but nevertheless metastasizes. Therefore, new predictive factors that improve risk stratification are needed. In this exploratory study, we investigated the potential of genome-wide DNA methylation profiling and copy number variation (CNV) analysis as additional prognostic tools for GISTs. We collected a cohort of 28 patients with GIST diagnosed between 2001 and 2022, with available follow-up and molecular data. This included 15 patients without progressive disease (seven low-risk and eight moderate- to high-risk GISTs) and 13 with progressive disease. Among those with progression, eight experienced recurrence or metastasis post-surgery (one low-risk, seven high-risk GISTs), while five had metastatic disease at initial diagnosis. Risk stratification was determined according to Miettinen's criteria. Genome-wide DNA methylation data and CNV plots were generated from imatinib-naïve primary GISTs using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised cluster analysis revealed distinct DNA methylation patterns predominantly associated with anatomical location and genotype. Differential DNA methylation analysis comparing primary gastric GISTs associated with and without progressive disease showed 8 differentially methylated regions spanning the coding and promoter areas of 6 genes. CNV analysis demonstrated that GISTs associated with progressive disease had the most CNVs, whereas low-risk, non-progressive GISTs had the fewest. Despite the limited sample size, this exploratory study indicates that genome-wide DNA methylation profiling and CNV analysis could enhance GIST risk stratification.

{"title":"Genome-Wide DNA Methylation and Copy Number Alterations in Gastrointestinal Stromal Tumors","authors":"Tony G. Kleijn,&nbsp;Baptiste Ameline,&nbsp;Roos F. Bleckman,&nbsp;Wierd Kooistra,&nbsp;Evert van den Broek,&nbsp;Gilles F. H. Diercks,&nbsp;Bettien M. van Hemel,&nbsp;Bert Timmer,&nbsp;Wim Timens,&nbsp;Gursah Kats-Ugurlu,&nbsp;Léon C. van Kempen,&nbsp;Boudewijn van Etten,&nbsp;Ed Schuuring,&nbsp;Albert J. H. Suurmeijer,&nbsp;Jacco J. de Haan,&nbsp;Daniel Baumhoer,&nbsp;Anna K. L. Reyners,&nbsp;Arjen H. G. Cleven","doi":"10.1002/gcc.70046","DOIUrl":"https://doi.org/10.1002/gcc.70046","url":null,"abstract":"<p>Gastrointestinal stromal tumors (GISTs) span a broad clinical spectrum, from indolent neoplasms to life-threatening metastatic tumors. A persistent limitation of current risk stratification systems is that a subset of GISTs is graded as low-risk but nevertheless metastasizes. Therefore, new predictive factors that improve risk stratification are needed. In this exploratory study, we investigated the potential of genome-wide DNA methylation profiling and copy number variation (CNV) analysis as additional prognostic tools for GISTs. We collected a cohort of 28 patients with GIST diagnosed between 2001 and 2022, with available follow-up and molecular data. This included 15 patients without progressive disease (seven low-risk and eight moderate- to high-risk GISTs) and 13 with progressive disease. Among those with progression, eight experienced recurrence or metastasis post-surgery (one low-risk, seven high-risk GISTs), while five had metastatic disease at initial diagnosis. Risk stratification was determined according to Miettinen's criteria. Genome-wide DNA methylation data and CNV plots were generated from imatinib-naïve primary GISTs using the Illumina Infinium MethylationEPIC BeadChip array. Unsupervised cluster analysis revealed distinct DNA methylation patterns predominantly associated with anatomical location and genotype. Differential DNA methylation analysis comparing primary gastric GISTs associated with and without progressive disease showed 8 differentially methylated regions spanning the coding and promoter areas of 6 genes. CNV analysis demonstrated that GISTs associated with progressive disease had the most CNVs, whereas low-risk, non-progressive GISTs had the fewest. Despite the limited sample size, this exploratory study indicates that genome-wide DNA methylation profiling and CNV analysis could enhance GIST risk stratification.</p>","PeriodicalId":12700,"journal":{"name":"Genes, Chromosomes & Cancer","volume":"64 3","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/gcc.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Germline Whole-Exome Sequencing in Non-Smoker Lung Cancer Patients Reveals Pathogenic Variants in Lung Cancer Driver Genes
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-03-22 DOI: 10.1002/gcc.70040
Giovanni Carapezza, Simone Paolo Minardi, Sara Noci, Giulia Pintarelli, Susanna Zanutto, Matteo Incarbone, Davide Tosi, Tommaso Antonio Dragani, Francesca Colombo, Marco Alessandro Pierotti, Manuela Gariboldi

Approximately 10%–15% of all lung cancers arise in non-smokers. Although there are no established aetiological factors, non-smokers with a family history of cancer have an increased risk of lung cancer, implying host genetic factors in lung cancer susceptibility. We sought to identify, in a cohort of 75 patients recruited before lung lobectomy, germline alterations with a strong association with lung cancer. Whole-exome sequencing was performed on genomic DNA from peripheral blood. Six resources were used to select pathogenic germline variants with strong clinical significance. In total, 33 pathogenic or likely pathogenic variants in 31 genes were identified. Of these, 13 were located in cancer-predisposing genes (nine were lung cancer drivers), most of which were involved in DNA repair mechanisms and diseases of metabolism. Among DNA repair-related genes, BRCA1 and BRCA2, and ATM have also been identified in other studies on non-smokers. Our results strongly support the hypothesis that a number of non-smoker lung cancer patients carry germline variants in cancer-predisposing genes, suggesting that lung cancer patients, particularly non-smokers, should be considered for germline molecular testing.

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引用次数: 0
SSX and SS18-SSX Antibodies as Additional Tools for Diagnosing Undifferentiated Neoplasms With the EWSR1::SSX3 Fusion
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-03-22 DOI: 10.1002/gcc.70044
Isidro Machado, Antonio Llombart-Bosch, Caterina Fumagalli, Cristina R. Antonescu
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引用次数: 0
Chromatin Interaction and Histone Mark Signatures Associated With TBXT Expression in Metastatic Lung Cancer
IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Pub Date : 2025-03-18 DOI: 10.1002/gcc.70041
Reuben M. Yaa, Brian M. Schilder, Rafael D. Acemel, Fiona C. Wardle

Background

TBXT, a member of the T-box transcription factor family, drives epithelial-to-mesenchymal transition in the metastasis of some cancers. However, the relationship between the epigenetic regulatory landscape and its expression in lung cancers remains elusive.

Methods

Circularized chromosome capture combined with sequencing (4C-seq) was employed to analyze physical chromatin interactions at the TBXT loci in the lung cancer cell line H460, a high TBXT-expressing cell line, compared to H358 and A549, which do not express TBXT. To define the regulatory landscape, the targeted TBXT chromatin interactions were integrated with histone modification profiles from respective cells, followed with motif analysis.

Results

Our analysis identified distinct patterns of potential cis-regulatory elements (pCREs) associated with the TBXT promoter, with increased near-cis pCRE enrichment in the TBXT-expressing cells. Integration of pCREs with epigenetic histone modification revealed two unique pCREs in TBXT-expressing H460 cells enriched with the active histone mark H3K27ac, harboring binding sites for transcription factors of the forkhead box, zinc finger, and musculoaponeurotic fibrosarcoma families that are linked to cancer metastasis.

Conclusion

Our findings shed light on active chromatin interactions with TBXT expression in lung cancers, pointing to specific DNA elements and regulatory proteins that may be involved. This knowledge paves the way for understanding TBXT expression dynamics at the onset and progression of metastatic cancers.

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引用次数: 0
期刊
Genes, Chromosomes & Cancer
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