Genes, Chromosomes & Cancer最新文献

Extraskeletal myxoid chondrosarcoma (EMC) is a rare mesenchymal neoplasm of uncertain histogenesis, characterized by recurrent gene fusions involving NR4A3 with various gene partners (EWSR1, TAF15, FUS, etc.). Although the impact of fusion variants has been linked to histology and prognosis, no study to date has comprehensively investigated the incidence and spectrum of secondary genetic alterations (SGAs) in EMC with regard to their association with fusion type and clinical impact. Our molecular database was searched for EMC tested on a hybridization capture-based targeted matched tumor-normal DNA NGS assay (MSK-IMPACT, 341-505 gene panel). All tumors had their fusion subtype confirmed either by Archer FusionPlex and/or fluorescence in situ hybridization (FISH). Clinicopathologic data was reviewed. Eighteen EMC patients (20 samples) were selected, with a mean age of 61 years and a male: female ratio of 5:1. By molecular testing, the most common NR4A3 fusion subtype involved EWSR1 (14/18, 78%), while two cases involved TAF15 gene partner, and one each TCF12 and FUS genes, respectively. All cases showed a low tumor mutation burden (TMB) (0–2, mean 0.83). Two-thirds of cases had concurrent SGAs, while the remaining showed only the driver NR4A3 fusion (0–8, mean 1.67 mut/case). Among the detected SGAs, only TP53 alterations were recurrent, seen in 2 cases with EWSR1::NR4A3 and TAF15::NR4A3 fusions, respectively. Other non-recurrent alterations involved CDKN1B, TERT, and MET genes, among others. Non-EWSR1 fusion variant tumors showed a tendency for a higher number of SGAs compared to EWSR1-rearranged tumors (mean 2.75 versus 1.36 mut/case). Patients with ≥ 1 SGA showed lower disease-free survival (DFS) (p = 0.022) and poor overall survival (OS) (p = 0.014), while no statistically significant correlation was detected between OS and fusion subtypes. Most patients (83%) developed distant metastases, which did not correlate with the SGA status. This is the first study addressing the genomic landscape in EMC with regard to prognostication beyond fusion subtypes and histology. Similar to other translocation-associated sarcomas, the number of co-occurring SGAs in EMC is low; however, when present, they are associated with worse survival. Although a higher number of SGAs showed a trend to be associated with non-EWSR1 fusion variants, larger multi-institutional studies are needed to further evaluate the correlation between fusion variants with SGAs and survival.

Hydatidiform moles represent abnormal pregnancies characterized by trophoblastic hyperproliferation. However, accurate diagnosis of partial hydatidiform moles (PHM) remains challenging. We present a rare case of a monozygotic androgenetic/biparental mosaic in a 26-year-old primigravida. The patient was referred to our institution for a suspected PHM, and ultrasonography revealed a nonviable embryo-like structure alongside villous formations with focal cystic changes. Pathological examination of the evacuated tissue revealed the coexistence of normal and hydropic villi. Histological assessment with p57KIP2 immunohistochemistry initially suggested PHM; however, some cytotrophoblasts and villous stromal cells were negative for p57KIP2 immunoreactivity. Therefore, we conducted short tandem repeat analysis separately for normal villous tissue and cystic villous lesions to elucidate the genetic origin of this unusual presentation. The normal villous portion exhibited biparental diploidy, whereas the cystic villous portion exhibited androgenetic monospermic patterns. Comparisons across all 16 loci revealed concordance between the paternal alleles of biparental diploid villi and the androgenic molar alleles, indicating a single sperm origin. SNP array analysis with B allele frequency plotting confirmed these findings at the whole-genome level; normal villi showed biparental diploid patterns, whereas cystic villi displayed uniparental disomic patterns. These results demonstrate that both components originated from a monozygotic conception rather than from dizygotic twinning. Therefore, we propose a clinical category based on the sequelae of endoduplication and the formation of a tripolar spindle apparatus through the first meiotic division, encompassing macroscopic androgenetic/biparental mosaicism, twin pregnancy with a hydatidiform mole, microscopic androgenetic/biparental mosaicism, and confined placental mosaicism. Given the presence of androgenetic elements and our institutional experience with gestational trophoblastic neoplasia development in a similar case, we recommend that such cases be managed according to complete hydatidiform mole surveillance protocols. This case highlights the diagnostic challenges posed by monozygotic androgenetic/biparental mosaic mechanisms and emphasizes the importance of molecular genetic analysis for the accurate diagnosis and appropriate clinical management of atypical hydatidiform moles.

Mastermind-like transcriptional coactivator (MAML) gene fusions have been documented in Thymic Epithelial Tumors (TETs). Specifically, lysine methyltransferase 2A (KMT2A)::MAML2 gene fusions are associated with type B2 and B3 thymomas. Here, we report for the first time a young patient with invasive type B3 thymoma harboring a novel KMT2A::MAML3 gene fusion. MAML3 and MAML2 are paralogues. In addition to the classic type B3 thymoma histology, this article documents intratumor heterogeneity, characterized by a trabecular and fascicular pattern, as well as areas of clear cells. Immunohistochemistry showed keratin positivity in tumor cells, while neuroendocrine markers were negative in trabecular regions. DNA-based next-generation sequencing failed to identify pathogenic variants, but RNA sequencing detected the KMT2A::MAML3 gene fusion. We compared the gene fusion sites of MAML2 and MAML3, focusing on exon 2, and found that they share similar functional protein domains. Moreover, the same domain appeared downstream of the KMT2A::MAML2 fusion protein. Therefore, we hypothesize that MAML3 gene fusions, like MAML2, lead to abnormal Notch signaling pathways and increase the invasive potential of certain thymoma subtypes. Our findings expand the genetic landscape of aggressive thymomas and offer new insights for molecular studies in TETs.