Genes, Chromosomes & Cancer最新文献

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that can locally recur and potentially metastasize. Approximately 50% of IMTs harbor rearrangements in the gene encoding anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase that can be therapeutically targeted with tyrosine kinase inhibitors (TKIs). With successful application of TKI in ALK-positive nonsmall cell carcinoma (NSCLC), ALK inhibitors are often first-line treatments for patients with unresectable or metastatic IMTs. Although acquired resistance to these agents may develop, resistance mechanisms are sparsely reported for IMTs. Here we report a case of a 71 year-old man with metastatic pulmonary IMT harboring a DCTN1::ALK fusion that progressed during alectinib TKI treatment. Whole exome sequencing of an enlarging metastatic lesion in right 4th rib revealed a novel p.V1180L mutation in the ALK tyrosine kinase domain as the mechanism of acquired resistance. To our knowledge, this is the first report of acquired p. V1180L mutation in IMTs treated with TKIs. In cases of ALK-positive IMTs that progress on TKI therapy, targeted sequencing for acquired ALK mutations may inform clinical decisions to adopt second-line therapeutic strategies.

Xanthogranulomatous epithelial tumor (XGET)/Keratin-positive giant cell tumor (KP-GCT) represents a spectrum of recently described neoplasms characterized by a proliferation of distinctive mononuclear cells expressing keratin within a background of osteoclast-like giant cells, mixed inflammatory cells, and a variably prominent xanthogranulomatous component. Recent studies demonstrated a recurrent HMGA2::NCOR2 fusion in many cases. We herein describe a case of XGET/KP-GCT arising in the right femoral head of a 19-year-old male harboring a rare novel HMGA2::COL14A1 fusion.

MN1 fusion is emerging as oncogenic in soft-tissue tumors. Here, we provided detailed clinicopathological documentation of a tumor with MN1::TAF3 fusion. The tumor developed on the face of an 8-year-old boy and did not recur or metastasize for 5 years after surgery without adjuvant therapy. Histologically, the tumor predominantly comprised sheets and nests of atypical, mildly pleomorphic epithelioid cells. Mallory body-like eosinophilic cytoplasmic inclusions, small round cells, and fascicles of spindle cells were focally observed. Mitotic activity was high, and focal necrosis was present. Immunohistochemically, the tumor was positive for cytokeratin AE1/AE3 in the epithelioid cell component but otherwise showed nonspecific phenotypes. Targeted RNA sequencing identified an in-frame MN1 (exon 1)::TAF3 (exon 3) fusion transcript. We validated the transcript with reverse transcription-polymerase chain reaction, Sanger sequencing, and MN1 break-apart fluorescence in situ hybridization. MN1::TAF3 was previously listed without details in a large-scale sequencing study involving a pediatric round cell sarcoma in the orbit, raising the possibility that these tumors might form a coherent group.

Most meningiomas are dural-based extra-axial tumors in close contact with the brain. Expression of genes and proteins at the tumor-brain interface in brain-invasive meningioma is basically unknown. Using the NanoString pan-cancer panel, differential expression of genes in the invasive edge versus main tumor body was determined in 12 invasive meningiomas (comprising the discovery cohort), and 6 candidate genes: DTX1, RASGRF1, GRIN1, TNR, IL6, and NR4A1, were identified. By immunohistochemistry, DTX1 and RASGRF1 expression correlated with gene expression, and were studied in an expanded cohort of 21 invasive and 15 noninvasive meningiomas, together with Ki-67. Significantly higher expression of DTX1, RASGFR1, and Ki-67 was found in the invasive edge compared with the main tumor body. Increased expression of RASGRF1 and Ki-67 was more clearly associated with brain invasion. The situation with DTX1 was less definitive since increased expression was observed in meningiomas both at the invasive edge and when in close contact with brain but without invasion. Pathway analyses identified significant links between DTX1 and RASGRF1 and key biological processes, including cell–cell adhesion, and signaling pathways including Notch, RAS, MAPK, and Rho. Higher expression of DTX1, RASGRF1, and Ki-67 in the brain-invasive area of meningiomas suggests that these proteins play a role in the process of brain invasion.

Plexiform fibromyxoma (PF) is a rare mesenchymal tumor that primarily occurs in gastric origin with a benign behavior. PF commonly harbors the MALAT1::GLI1 fusion gene. Here, we describe a case of a 36-year-old female with a PF. Abdominal computed tomography (CT) showed a 3.3 cm mass in the stomach. She underwent laparoscopic partial gastrectomy. Immunohistochemistry (IHC) of the tumor revealed strongly positive staining for CD34, SDHB, STAT6, MDM2, and CDK4. And the tumor showed TP53 mutant expression. Next-generation sequencing (NGS) comprehensive genomic profiling identified GLI1, CDK4, and MDM2 co-amplification and TP53 mutations. Here, we first report a case of a young woman with a PF harboring co-amplification of GLI1, CDK4, and MDM2 genes. The patient underwent complete removal of the tumor without the use of radiotherapy or chemotherapy. No recurrence was observed during the follow-up period of 8 months. This study aims to improve our understanding of PF by analyzing the clinicopathological characteristics of this case, including immunohistochemical (IHC) and genetic examination, and reviewing relevant literature.

With no more than two dozen cases reported in the literature, malignant peripheral nerve sheath tumor (MPNST) is a rare primary mesenchymal neoplasm arising in the female genital tract. Most cases occurred in middle-aged adults with high grade histology, unfavorable clinical outcome, and no history of neurofibromatosis type 1. Its extreme rarity in this site no doubt poses a diagnostic challenge during routine clinical practice. In the following, we report an additional case of uterine MPNST occurring in a 49-year-old Chinese woman, which was initially misdiagnosed as a leiomyosarcoma. The primary tumor showed two distinctive components—a high-grade poorly differentiated component with markedly pleomorphic spindle cells arranged in a peritheliomatous pattern; and a leiomyosarcoma-like (LMS-like) component with tumor cells displaying obvious myoid differentiation. The patient suffered a recurrence less than 2 years later with the recurrent tumor demonstrating similar features to the high-grade component of the primary tumor. The patient eventually succumbed 46 months later after developing another recurrence despite receiving targeted therapy and chemotherapy. On retrospective molecular analysis, no clinically relevant fusion transcript was detected on RNA sequencing. Interestingly instead, DNA methylation analysis showed the tumor clustered with the “MPNST” group in the German Cancer Research Center (DKFZ) sarcoma classifier. The tumor was also found to have EED gene homozygous deletion, multiple copy number alterations and loss of H3K27me3 expression in both high-grade and LMS-like components. Combining histology with all the ancillary tests results, the diagnosis was most consistent with MPNST. Our case highlights the diagnostic pitfalls for MPNST arising in the female genital tract and the potential clinical utility of DNA methylation analysis.

Angiosarcoma (AS) is a malignant vascular neoplasm comprising neoplastic endothelial cells accounting for 1%–4% of soft tissue sarcomas. While lymphedema-associated and post-irradiation ASs are almost always driven by a high-level amplification of MYC (8q24), sporadic ASs, including those of breast parenchymal origin, typically lack MYC amplification. Here, we report a case of sporadic breast MYC-amplified AS in a 19-year-old female with no history of lymphedema or irradiation, who was referred to our hospital for an enlarging right breast mass. After needle biopsy, the patient underwent right mastectomy and axillary lymphadenectomy. Microscopically, atypical endothelial cells proliferated and formed well-defined or slit-like vascular channels that invaded and dissected the breast parenchymal fat, ducts, and lobules. In a limited area, the tumor cells showed solid sheet-like proliferation with increased mitotic figures of 40 per 2 mm² with a small area of necrosis. Immunohistochemical analysis revealed strong positivity for c-Myc. Fluorescence in situ hybridization (FISH) with MYC break-apart probes showed a high-level 5′ single signal amplification. The patient was disease-free 16 months post-surgery. Nanopore sequencing successfully detected not only a high-level amplification of the 8q24 region, including MYC, but also multiple structural variants of the 8q24 region. In-depth analysis revealed extrachromosomal circular DNA amplification including the MYC protein-coding region and upstream region but not the downstream region. We also performed methylation classification using nanopore-based methylation data to successfully categorize the tumor as AS. This case report highlights the potential utility of nanopore sequencing in the diagnosis of sarcomas.