23 research outputs found
Association of EWS-FLI1 Type 1 Fusion with Lower Proliferative Rate in Ewing’s Sarcoma
The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal
tumor (PNET), is defined genetically by specific chromosomal translocations
resulting in fusion of the EWS gene with a member of the ETS family of
transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of
molecular genetic heterogeneity stems from the variation in the location of the
translocation breakpoints, resulting in the inclusion of different combinations
of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type
of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis
and appears to encode a functionally weaker transactivator, compared to other
fusion types. We sought to determine whether the observed covariation of
structure, function, and clinical course correlates with tumor cell kinetic
parameters such as proliferative rate and apoptosis, and with expression of the
receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with
defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG),
we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n
= 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining
with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with
EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a
continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression
analysis suggests that this association was secondary to the association of type
1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG
cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney
test; P = 0.02, Fisher's exact test), but there was no significant difference in
IGF-1R. TUNEL results showed no significant differences between groups. Our
results suggest that clinical and functional differences between alternative
forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly
mediated by differential regulation of the IGF-1R pathway
TFG-MET fusion in an infantile spindle cell sarcoma with neural features
Item does not contain fulltextAn increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma. Here, we report an unusual spindle cell sarcoma presenting as a large and infiltrative pelvic soft tissue mass in a 4-month-old girl, which revealed a novel TFG-MET gene fusion by whole transcriptome RNA sequencing. The tumor resembled the morphology of an infantile fibrosarcoma with both fascicular and patternless growth, however, it expressed strong S100 protein immunoreactivity, while lacking SOX10 staining and retaining H3K27me3 expression. Although this immunoprofile suggested partial neural/neuroectodermal differentiation, overall features were unusual and did not fit into any known tumor types (cellular schwannoma, MPNST), raising the possibility of a novel pathologic entity. The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation. The discovery of this new fusion is significant since the resulting MET activation can potentially be inhibited by targeted therapy, as MET inhibitors are presently available in clinical trials
Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature
Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This "ISA" methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification
Basal cell adenocarcinoma of the palate with squamous metaplasia
Basal cell adenocarcinoma is a rare salivary gland tumour, especially in minor glands. The clinical, histological, and immunohistochemical features of a case involving the palate are described. Formalin fixed, paraffin embedded sections of the tumour were examined in haematoxylin and eosin (H&E) sections and also using immunostaining for cytokeratins 7, 8, 13, 14, 18, 19, vimentin, muscle specific actin (HHF35), and laminin. H&E sections showed that the tumour was composed mainly of basaloid cells and a striking feature was the presence of squamous metaplasia. Neural invasion was also conspicuous. Immunohistochemical reactions indicated that cytokeratin 14 was expressed by all tumour cells and vimentin by all cells except those in the areas of squamous metaplasia. The remaining cytokeratins and actin were present in some of the tumour cells, while laminin showed discreet positivity around cell arrangements. The foci of squamous metaplasia and the immunohistochemical findings are helpful in distinguishing basal cell adenocarcinoma from other salivary gland tumours which show basaloid cells. Key Words: basal cell adenocarcinoma • salivary gland neoplasm