"Genes, Chromosomes and Cancer"

Glaser, Selina; Wagener, Rabea; Kretzmer, Helene; López, Cristina; Baptista, Maria Joao; Bens, Susanne; Bernhart, Stephan; Bhatia, Kishor; Borkhardt, Arndt; Elgaafary, Shaymaa; Hoffmann, Steve; Hübschmann, Daniel; Hummel, Michael; Klapper, Wolfram; Kolarova, Julia; Kreuz, Markus; Lazzi, Stefano; Löffler, Markus; Navarro, Jose Tomas; Neequaye, Janet; Onyango, Noel; Onyuma, Timothy; Ott, German; Radlwimmer, Bernhard; Rohde, Marius; Rosenwald, Andreas; Rosolowski, Maciej; Schlesner, Matthias; Szczepanowski, Monika; Tapia, Gustavo; Wößmann, Wilhelm; Küppers, Ralf; Trümper, Lorenz; Leoncini, Lorenzo; Lichter, Peter; Val, Coral; Ammerpohl, Ole; Burkhardt, Birgit; Mbulaiteye, Sam M.; Siebert, Reiner; ,

doi: 10.1002/gcc.70042pmid: 40192513

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.

doi: 10.1002/gcc.70047pmid: N/A

Vega‐Gonzalez, Jesus; Toro, Jose Antonio Cortés; García, Esthefanía Latorre; Marquina, Gloria; Serrano, Montserrat de la Torre; Gallardo, Ana María Colino; Giménez, Reyes Bergillos; Martínez, Desiré Hernández; Egido, Alejandro García; García, Lorenzo Alarcón; Nielsen, Lone; Plaza, Jose Carlos; Medina, Luis Ortega

doi: 10.1002/gcc.70048pmid: 40207937

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.

Ta, Minh Chau; Gandon, Camille; Mancini, Maxence; Lantier, Philippe; Mercier, Olaf; Mourah, Samia; Battistella, Maxime

doi: 10.1002/gcc.70049pmid: 40249078

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.

Rullo, Emma; Barresi, Sabina; Rossi, Sabrina; Patrizi, Sara; Miele, Evelina; Barisella, Marta; Casanova, Michela; Ferrari, Andrea; Chiaravalli, Stefano; Pelizzo, Gloria; Alaggio, Rita

doi: 10.1002/gcc.70032pmid: 40178433

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.