Pediatric SMARCB1/INI1-deficient poorly differentiated chordoma of the skull base: report of five cases and review of literature / 中华病理学杂志

Objective: To investigate the clinicopathological characteristics and differential diagnosis of pediatric SMARCB1/INI1-deficient poorly differentiated chordoma (PDC) of the skull base. Methods: Five cases of SMARCB1/INI1-deficient PDC were identified in 139 cases of chordoma diagnosed in Sanbo Brain Institute, Capital Medical University, Beijing, China from March 2017 to March 2021. The clinical and imaging data of the 5 PDCs were collected. H&E and immunohistochemical staining, and DNA methylation array were used, and the relevant literatures were reviewed. Results: All 5 PDCs were located at the clivus. The average age of the patients was 6.4 years, ranging from 3 to 16 years. Three patients were female and two were male. Morphologically, in contrast with classical chordomas, they presented as epithelioid or spindle tumor cells organized in sheets or nests, with necrosis, active mitoses, and infiltration into surrounding tissue. All cases showed positivity of CKpan, EMA, vimentin and brachyury (nuclear stain), and loss of nuclear SMARCB1/INI1 expression. S-100 protein expression was not frequent (2/5). Ki-67 proliferative index was high (20%-50%). All cases had over-expressed p53. It was necessary to differentiate SMARCB1/INI1-dificient PDC from SMARCB1/INI1-dificient tumors occurring at skull base of children or the tumors with epithelial and spindle cell morphological features. The 3 PDCs with DNA methylation testing showed the methylation profiles different from the pediatric atypical teratoid/rhabdoid tumors. They formed an independent methylation profile cluster. The clinical prognosis of the 5 patients was poor, and the overall survival time was 2-17 months. Conclusions: PDC is a special subtype of chordoma, which often affects children and occurs in the clivus. The PDC shares epithelioid or spindle cell morphologic features which are different from the classic chordoma. Besides the typical immunohistochemical profile of chordoma, PDC also has loss of nuclear SMARCB1/INI1 expression and distinct epigenetic characteristics.

Metastatic poorly differentiated chordoma: the eyes do not see what the mind does not know

Chordoma is a rare tumor. It has unique clinical, pathological and immunohistochemical characteristics. Accurate diagnosis is essential as the tumor shows an aggressive clinical course and requires a multimodal therapeutic approach. A case with wide spread distant metastatic disease that was initially thought to represent metastatic thyroid carcinoma is presented. Appropriate clincopathologic correlation and the histologic findings raised the possibility of poorly differentiated chordoma. The diagnosis was confirmed by immunohistochemistry for INI-1 and Brachyury. The approach to the diagnosis emphasizing the clinical and pathologic findings of this case is discussed and reviewed in the context of the published literature.

Molecular genetics and immunophenotype of INI1/SMARCB in epithelioid sarcoma / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the immunophenotype and molecular genetics of epithelioid sarcoma (ES), INI1 expression and its role in differential diagnosis.</p><p><b>METHODS</b>Twenty cases of ES were retrieved from the archival files and selected for immunohistochemical study, DNA sequencing and fluorescence in-situ hybridization. The clinical and pathologic features were also reviewed.</p><p><b>RESULTS</b>The age of patients ranged from 16 to 75 years (mean = 40.2 years). The median age of patients in classic ES and proximal-type was 37.9 years and 42.0 years, respectively. The male-to-female ratio was 1.2: 1.0. Classic ES mostly occurred in the extremities while proximal-type ES often affected the perineum and external genitalia and trunk. Histologically, granuloma-like structures, consisting of aggregates of epithelioid and spindly tumor cells with central necrosis, were observed in classic ES. The epithelioid tumor cells contained abundant eosinophilic cytoplasm, merged with spindly cells at the periphery and admixed with collagen fibers. In proximal-type ES, the tumor cells showed prominent epithelioid and/or rhabdoid features, had marked cytologic atypia and grew in multinodular or diffuse patterns. In 2 cases of proximal-type ES studied, the "rhabdoid" tumor cells demonstrated a diffuse sheet-like growth pattern, mimicking malignant rhabdoid tumor. Immunohistochemical study showed that vimentin was positive in all cases. Pan-cytokeratin, CK8, CK7, epithelial membrane antigen and CD34 were expressed in 16, 15, 1, 18 and 13 cases, respectively. The staining for S-100 protein was focal and weak in 5 cases. None of the cases studied expressed CD31 and HMB45. Loss of INI1 was demonstrated in 10 of the 13 classic ES cases and 5 of the 7 proximal-type ES cases. The mutation of INI1 gene was detected in 1 of the 6 cases. Deletion of INI1 gene including heterozygous deletion, homozygous deletion and haploid was observed in 8 of the 11 cases.</p><p><b>CONCLUSIONS</b>Owing to the histologic heterogeneity, pitfalls in diagnosis of ES sometimes are encountered. INI1 is lost in most cases of ES. Immunohistochemical study, including staining for INI1, provides useful clues in pathologic diagnosis. Instead of INI1 mutation, inactivation of INI1 gene related deletion is not uncommon.</p>

Changes in gene expression profiles in multiple myeloma cells after knocking-down SNF5, a core subunit of SWI/SNF complex / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the changes in the gene expression profiles in a multiple myeloma cell line after knocking-down the expression of SNF5, a core component of the SWI/SNF chromatin remodeling complex.</p><p><b>METHODS</b>The total RNA were extracted from tetracycline-inducible SNF5 knockdown (KD) cell line derived from KM3 cells for gene expression profiling by affymetrix microarray and bioinformatic analysis.</p><p><b>RESULTS</b>Knockdown of SNF5 inhibited KM3 cell proliferation. A total of 545 genes were found to be differentially expressed in the cells with SNF5 knockdown, among which 214 were up-regulated and 331 were down-regulated.</p><p><b>CONCLUSIONS</b>SNF5 is essential for the growth of multiple myeloma cells and can regulate the expression of the genes associated with cell growth and apoptosis.</p>

Integrase interactor 1 regulates proliferation, apoptosis and invasion in gastric cancer cells / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Integrase interactor 1 (INI1), which encodes a component of the ATP-dependent chromatin remodeling hSWI-SNF complex, has been identified as a tumor suppressor in many tumors. Nonetheless, the role of INI1 in gastric tumor progression is not known exactly. The aim of this research was to investigate the effect of INI1 in the carcinogenesis and progression of gastric cancer.</p><p><b>METHODS</b>Gastric tumor tissues with different differentiation levels from clinical gastric carcinoma samples and adjacent control normal tissues were taken. Expression levels of INI1 were detected by quantitative reverse transcriptation-polymerase chain reaction (RT-PCR) and Western blotting. Gastric cancer cell line SGC7901 was transfected with INI1 eukaryotic expressing vector INI1-GFP. Cell proliferation activities were assessed by MTT; cell count and cell cycle were detected by flow cytometry (FCM); cell apoptosis were measured by TUNEL and FCM; cell migration and invasiveness were evaluated by wound healing and transwell assays. Expression levels of INI1 and proliferation-related genes including p16, p21, cyclin D1 and cyclin A, apoptosis genes p53, B-cell non-Hodgkin lymphoma-2 (Bcl-2), Bcl-2-associated x protein (Bax) and caspase-3, and invasion-related genes including intercellular adhesion molecule 1 (ICAM1), matrix metalloproteinase 2 (MMP2), MMP9 and tissue inhibitor of matrix metalloproteinase 1 (TIMP1), were detected by quantitative RT-PCR and Western blotting.</p><p><b>RESULTS</b>INI1 expression levels were lower in gastric carcinoma compared with adjacent control normal tissues. Overexpression of INI1 in SGC7901 cells inhibited its proliferation and invasiveness, but increased anoikis and G(0)/G(1) cell number. INI1-GFP transfection upregulated expression of INI1 and proliferation related genes p16 and p21, apoptosis genes p53 and Bax, and invasion-related genes TIMP1; cyclin D1, cyclin A, Bcl2, ICAM1, MMP2 and MMP9 were downregulated, and there was no significant change in caspase 3 levels.</p><p><b>CONCLUSION</b>INI1 plays a key role in gastric carcinogenesis by affecting proliferation, apoptosis and invasion.</p>

Effect of PIH1D1 on the degradation of its binding protein SNF5 / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the effects of PIH1D1 on its binding protein SNF5, a core subunit of the SWI/SNF chromatin remodeling complex.</p><p><b>METHOD</b>The degradation pathway of SNF5 was identified with protein synthesis inhibitor cycloheximide (CHX) and a potent proteasome inhibitor MG132, and then the PIH1D1 eukaryotic expression plasmid was transfected to explore its effect on the stability of SNF5.</p><p><b>RESULTS</b>HEK293T cells were effectively treated with CHX (optimal concentration: 400 microg/ml) and MG132 (optimal concentration: 20 mmol/L). The degradation of SNF5 was mediated by the proteasome pathway. PIH1D1 regulated the protein level of SNF5 by attenuating its proteasome degradation.</p><p><b>CONCLUSION</b>PIH1D1 may stabilize SNF5 by attenuating its proteasome degradation pathway.</p>

Screening, cloning, and analyzing for hSNF5 binding proteins in human fetal brain / 中国医学科学院学报

<p><b>OBJECTIVE</b>To identify novel binding proteins of hSNF5, a subunit of chromatin remodeling complex in human fetal brain.</p><p><b>METHODS</b>The yeast two-hybrid system was used for this study. Positive cDNA clones were sequenced. Sequence homology and putative functional domains were analyzed and compared with databank.</p><p><b>RESULTS</b>Nine positive clones obtained were analyzed, among which the sequence of one clone was 97% homologous to the 3' mRNA of a hypothetical protein FLJ20643, while other four clones were related to protein coding sequences existed in the GenBank. The rest four clones were not in frame with any known protein coding sequence.</p><p><b>CONCLUSIONS</b>Clones encoding for hSNF5 binding protein exists in cDNA library of human brain. These proteins may recruit chromatin remodeling complex via hSNF5 to modulate the transcription of their target gene and the related cell functions.</p>