Genes, Chromosomes & Cancer最新文献

Molecular testing has significantly transformed the field of anatomic pathology over the past several decades. Despite these advances, acral mesenchymal neoplasms remain diagnostically challenging, requiring careful integration of clinical presentation, histologic features, and molecular findings for accurate classification. Herein, we present a case of an acral chondromyxoid mesenchymal neoplasm harboring a novel in-frame TCF4::ERG fusion involving the right index finger of a 26-year-old female. Morphologically, this tumor consisted of nests and sheets of monotonous small round-to-ovoid cells embedded in a background of chondromyxoid stroma and hyalinized collagen. The tumor cells were diffusely CD34, ERG, and focally p63 reactive, while S100 protein, cytokeratin AE1/AE3, Pan-TRK, ALK, smooth muscle actin, and desmin were negative. Albeit short follow-up (3 months), the patient continues to do well without evidence of metastasis or local recurrence.

A range of genomic drivers have been identified in schwannomas, including a number of translocations, most commonly SH3PXD2A::HTRA1. To date, despite the analysis of large numbers of cases, no examples of variant HTRA1 partners have been described. We describe a schwannoma arising in the periportal region in which a novel TANC1::HTRA1 fusion was identified. The identification of this variant expands the range of fusion drivers in schwannoma and offers insight into the pathogenic mechanism of HTRA1 fusions and their utility in molecular diagnosis.

Structural genomic variants leading to anaplastic lymphoma kinase (ALK) gene fusions and aberrant expression of the ALK tyrosine kinase are the hallmark of subtypes of T- and B-lineage neoplasms, namely ALK-positive anaplastic large lymphoma (ALCL) and ALK-positive large B-cell lymphoma (LBCL). The latter is a rare aggressive lymphoma, which has been initially identified as a variant of diffuse LBCL (DLBCL) with plasmablastic features. Here, we performed comparative DNA methylation profiling of human and murine ALK-positive B-cell neoplasms. Array-based DNA methylation data from ALK-positive LBCL samples of eight patients were compared to that of DLBCL (n = 75), multiple myeloma (MM, n = 24), ALK-positive ALCL (n = 12) and normal B-cell populations (n = 93). ALK-positive LBCLs share a distinct DNA methylation signature similar to that of MM, characterized by lower global DNA methylation levels compared to DLBCLs and normal B-cell populations. DNA methylation alterations in ALK-positive LBCL were predominantly located in heterochromatic and polycomb-repressed regions. The epigenetic age and relative proliferative history of ALK-positive LBCL were intermediate between MM and DLBCL. B-cell neoplasms in NPM::ALK transgenic mice showed a similar hypomethylated signature when compared to normal murine B cells. Cross-species comparison indicated conservation of chromatin states and pathways affected by hypomethylation. Together, the findings suggest that in line with their phenotypical appearance human and murine ALK-positive B-cell lymphomas share an epigenetic profile more closely resembling that of plasma cell neoplasias than that of DLBCLs.

Recurrent KMT2A and YAP1 related fusions have recently been reported in various mesenchymal neoplasms of different histogenesis. First, YAP1::KMT2A fusions have been described in a subset of MUC4-negative sclerosing epithelioid fibrosarcomas (SEF), while VIM::KMT2A fusions in a handful of cases associated with an undifferentiated spindle cell phenotype lacking stromal hyalinization. On the other hand, YAP1 gene rearrangements have been reported in a wide spectrum of sarcomas, including vascular neoplasms such as epithelioid hemangioendothelioma (EHE). Despite these molecular advances, occasional challenges in classification may occur even if the pathognomonic fusion is identified. In this study, we report such a case of a soft tissue sarcoma displaying an unusual morphology and immunoprofile, which remained unclassified even after a YAP1::KMT2A fusion was detected. The lesion occurred in the left leg of a 65-year-old female and microscopically closely resembled a SEF, with epithelioid morphology organized in cords, nests, and sheets in a heavy hyalinized background. Focally, the cells showed cytoplasmic vacuoles with eosinophilic material, reminiscent of the “blisters cells” seen in EHE. Moreover, by immunohistochemistry (IHC), the tumor showed diffuse reactivity for vascular markers, including ERG, CD31, CD34, and D2-40, as well as for TFE3, while being negative for MUC4, CAMTA1, smooth-muscle actin, desmin, S100 and keratins. Targeted RNA sequencing revealed a YAP1::KMT2A fusion. Based on this molecular result and the conflicting morphologic and IHC findings, a definitive distinction between a MUC4-negative SEF and an EHE could not been established. To further subclassify the lesion, subsequent clustering analysis using RNAseq signature was performed against a vast group of sarcoma types on the same array. Results showed that the tumor was in close proximity to the SEF group, admixed together with the other YAP1::KMT2A MUC4 negative SEF sarcomas. This case is highly instructive, as it shows another application of RNA sequencing in clinical practice when discordant or uncertain results between pathologic findings and fusion type may occur. Indeed, RNAseq signature could help, in this context, to better classify the tumor as a YAP1::KMT2A sarcoma instead of a vascular tumor. Larger series are needed to evaluate the pathogenesis of these tumors and the relevance of vascular markers expression.

J. Vega-Gonzalez, J. A. C. Toro, E. L. García, G. Marquina, M. d. l. T. Serrano, A. M. C. Gallardo, R. B. Giménez, D. H. Martínez, A. G. Egido, L. A. García, L. Nielsen, J. C. Plaza, and L. O. Medina, “EWSR1::SSX1 Fusion-Driven Synovial Sarcoma: A Case Presentation and Review of the Literature,” Genes Chromosomes Cancer 64 (2025): e70048, https://doi.org/10.1002/gcc.70048.

This article was originally published with the incorrect article category of “Review Article.” The correct category is Brief Report. This has been corrected in the online version of the article.

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