Genes, Chromosomes & Cancer最新文献

The integration of next generation sequencing into clinical practice has revolutionized the diagnosis of soft tissue tumors, enabling the discovery of novel tumor entities. We encountered a group of unclassified fibromyxoid mesenchymal neoplasms harboring biallelic NF1 loss of function (LOF) mutations, lacking features of neurofibroma or neurofibromatosis. The tumors were investigated by immunohistochemistry (IHC), targeted DNA and RNA sequencing and DNA methylation profiling. All cases occurred in male patients aged 4–76 years (median, 53 years). Tumor sites included the thigh (2), pelvis (2), and retroperitoneum (1), with size range of 5.7–12.2 cm (median, 9.1 cm). The tumors were well-demarcated with minimal infiltration of adjacent tissue and shared morphologic features. The stroma ranged from predominantly myxoid, fibromyxoid to mostly fibrous. Tumor cells were spindle with scant cytoplasm and ovoid nuclei with fine chromatin and inconspicuous nucleoli. Mitoses were rare (≤ 2/2 mm²), and necrosis was absent. IHC findings were largely nonspecific, with variable CD34 staining and lack of neural markers expression. All cases harbored NF1 LOF, four were somatic, and one was germline, all with accompanying loss of heterozygosity (LOH), leading to biallelic inactivation. No other recurrent somatic alterations were identified. Tumor mutational burden was consistently low, while fraction of genome altered was high, ranging from 0.25 to 0.93 (median, 0.46). Allele-specific copy number analysis showed widespread LOH in four of five cases (> 70%). The remaining case demonstrated a high but subthreshold LOH (38%). Targeted RNA sequencing, performed in four cases, was negative for fusions. Dimensionality reduction of DNA methylation placed four cases in a distinct cluster near well-differentiated/dedifferentiated liposarcoma, while the remaining case was placed near malignant peripheral nerve sheath tumor. All patients underwent surgical resection. Two patients developed local recurrences and are alive with disease, while the remaining three had no evidence of disease. We describe an unclassified fibromyxoid mesenchymal neoplasm of uncertain malignant potential characterized by recurrent biallelic NF1 LOF and widespread genomic LOH.

The increasing application of molecular diagnostics in pathology has enabled the identification of novel tumor entities, including clear cell tumor with MITF::CREM translocation, as recognized in the 5th edition of the WHO Classification of Tumours. We describe a case involving a 2-year-old boy with a left scalp lesion, initially suspected clinically to represent a pyogenic granuloma. Histopathological assessment, corroborated by molecular analysis, established the diagnosis of clear cell tumor with MITF::CREM translocation. This case emphasizes the need to consider rare entities in the differential diagnosis of dermal lesions and highlights the critical role of molecular testing in diagnostic precision. Notably, this molecularly defined neoplasm demonstrated no immunohistochemical evidence of melanocytic differentiation, contrasting with the features described in the WHO classification.

Hereditary paragangliomas (PGLs) caused by germline SDHD pathogenic variants (PVs) exhibit a parent-of-origin effect, with tumors arising almost exclusively when the PV is inherited from the paternal allele. The Hensen model proposes that a cluster of maternally expressed tumor suppressor genes (TSGs) on chromosome 11p15.5 may play a crucial role in SDHD-related PGL tumorigenesis, wherein somatic loss of maternal 11p and wild-type SDHD allele, in conjunction with a paternally inherited SDHD PV, triggers tumor development. To systematically localize and identify the most crucial maternal-expressed TSGs within 11p15.5, we developed a novel single nucleotide variant (SNV)-oriented, capture-based targeted enrichment approach followed by next-generation sequencing (NGS) to enable high-resolution loss-of-heterozygosity (LOH) analysis. Among 13 SDHD-related PGLs and 23 non-SDHD-related PGLs, a somatic loss of 11p15.5-15.4 was detected in 92% and 47%, respectively, a significant difference (p = 0.0035). Parental genotype analysis confirmed that the lost chromosome was of maternal origin. In our studies, 12/13 SDHD-related tumors demonstrated complete loss of the maternal 11p15.5-15.4 region, preventing localization of a specific driver TSG. Only one exceptional SDHD-related tumor retained this region, warranting further investigation into the mechanism underlying parent-of-origin tumorigenesis.

We report a GLI1-altered mesenchymal tumor of the duodenum with a novel TNFAIP3::GLI1 gene fusion, deceptive morphology, and late recurrence. The patient was a 72-year-old female who was found to have a polypoid 3.7 cm duodenal mass which, based on epithelioid morphology and focal immunoreactivity for cytokeratin, was diagnosed as invasive adenocarcinoma following review by an academic consultant. Sixty-seven months later, the patient presented with multiple liver nodules representing metastatic disease. RNA sequencing demonstrated a novel TNFAIP3::GLI1 gene fusion in the liver lesion, which had higher mitotic activity but showed similar pure epithelioid morphology and immunophenotype as the original small bowel lesion. In addition to expanding the spectrum of GLI1-associated gene fusions, this case highlights the potential for misdiagnosis of epithelioid GLI1-altered mesenchymal tumors as adenocarcinoma (particularly given the variable immunoreactivity for cytokeratin), and the need for long-term follow up of these typically slowly growing neoplasms.

Tumor cell plasticity plays a key role in the progression of malignant neoplasms and therapy resistance, yet its spatial dynamics remain poorly understood. This study investigates the spatial distribution of epithelial–mesenchymal transition (EMT) and stemness, and their prognostic relevance in lung adenocarcinoma (LUAD). Single-cell RNA sequencing was performed on 10 tumor fragments from three regions (core, core-adjacent, and edge) of a single LUAD using a SURFSeq 5000 platform. Stemness potential was identified by CytoTRACE2, EMT by UCell and the Hallmark_epithelial_mesenchymal_transition signature, and tumor cells associated with disease prognosis by Scissor. LUAD displayed pronounced spatial heterogeneity of tumor cell plasticity. Stemness potential was heightened at the edge, while EMT was most prominent in the core. The correlation between EMT and stemness was slightly higher at the edge, though it remained negligible (R = 0.17, p = 5.5e⁻⁷). Higher EMT scores were observed in tumor cells associated with poor overall survival (r = 0.433, p < 2e⁻¹⁶), whereas stemness was prevalent in tumor cells associated with poor progression-free survival (r = 0.251, p = 7.15e⁻⁶). Tumor cells associated with poor prognosis were enriched with the MYC-targets v1 signature with PCBP1 and PA2G4 as the top contributing genes. Immunohistochemical data showed that PCBP1 and PA2G4 proteins predominantly localized within tumor cells of LUAD. Taken together, these findings highlight the spatial heterogeneity of tumor cell plasticity features in LUAD and uncover biomarkers associated with poor prognosis.

Ubiquitin-specific protease 6 (USP6)-associated neoplasms constitute a spectrum of related entities that share clinical and morphological characteristics. They are defined molecularly by the presence of a USP6 gene rearrangement that results in promoter swap fusions involving a range of partner genes that activate expression of full-length USP6. In this study, we retrospectively reviewed whole transcriptome results and identified USP6-associated neoplasms in the St. Jude clinical genomics cohort, with a focus on novel fusion partners. Three patients (ages 4–21 years) presented with bone lesions affecting the humerus, femur, and distal femur, respectively. Histological examination revealed characteristic aneurysmal bone cyst (ABC) features including cystic spaces, osteoclastic giant cells with smooth muscle actin positivity in myofibroblastic cells, and at least one case with prominent myxoid features. Clinical whole transcriptome RNA sequencing identified three previously unreported USP6 fusions including SEC24D::USP6, HNRNPC::USP6, and ERRFI1::USP6. All fusions resulted in transcriptional upregulation of USP6. In this report, we summarize the clinical, radiographic, and histologic presentations of these new cases and describe the associated fusion structures.