78 research outputs found
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Well-differentiated papillary mesothelioma of the peritoneum is genetically defined by mutually exclusive mutations in TRAF7 and CDC42.
Well-differentiated papillary mesothelioma is an uncommon mesothelial neoplasm that most frequently arises in the peritoneal cavity of women of reproductive age. Whereas malignant mesothelioma is an aggressive tumor associated with poor outcome, well-differentiated papillary mesothelioma typically exhibits indolent behavior. However, histologically differentiating between these two entities can be challenging, necessitating the development of distinguishing biomarkers. While the genetic alterations that drive malignant mesothelioma have recently been determined, the molecular pathogenesis of well-differentiated papillary mesothelioma is unknown. Here we performed genomic profiling on a cohort of ten well-differentiated papillary mesothelioma of the peritoneum. We identified that all tumors harbored somatic missense mutations in either the TRAF7 or CDC42 genes, and lacked alterations involving BAP1, NF2, CDKN2A, DDX3X, SETD2, and ALK that are frequent in malignant mesothelioma. We recently identified that another mesothelial neoplasm, adenomatoid tumor of the genital tract, is genetically defined by somatic missense mutations in the TRAF7 gene, indicating a shared molecular pathogenesis between well-differentiated papillary mesothelioma and adenomatoid tumors. To the best of our knowledge, well-differentiated papillary mesothelioma is the first human tumor type found to harbor recurrent mutations in the CDC42 gene, which encodes a Rho family GTPase. Immunohistochemistry demonstrated intact BAP1 expression in all cases of well-differentiated papillary mesothelioma, indicating that this is a reliable marker for distinguishing well-differentiated papillary mesothelioma from malignant mesotheliomas that frequently display loss of expression. Additionally, all well-differentiated papillary mesothelioma demonstrated robust expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation, similar to that observed in adenomatoid tumors. In contrast, we have previously shown that L1CAM staining is not observed in normal mesothelial cells and malignant mesotheliomas of the peritoneum. Together, these studies demonstrate that well-differentiated papillary mesothelioma is genetically defined by mutually exclusive mutations in TRAF7 and CDC42 that molecularly distinguish this entity from malignant mesothelioma
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Adenomatoid tumors of the male and female genital tract are defined by TRAF7 mutations that drive aberrant NF-kB pathway activation.
Adenomatoid tumors are the most common neoplasm of the epididymis, and histologically similar adenomatoid tumors also commonly arise in the uterus and fallopian tube. To investigate the molecular pathogenesis of these tumors, we performed genomic profiling on a cohort of 31 adenomatoid tumors of the male and female genital tracts. We identified that all tumors harbored somatic missense mutations in the TRAF7 gene, which encodes an E3 ubiquitin ligase belonging to the family of tumor necrosis factor receptor-associated factors (TRAFs). These mutations all clustered into one of five recurrent hotspots within the WD40 repeat domains at the C-terminus of the protein. Functional studies in vitro revealed that expression of mutant but not wild-type TRAF7 led to increased phosphorylation of nuclear factor-kappa B (NF-kB) and increased expression of L1 cell adhesion molecule (L1CAM), a marker of NF-kB pathway activation. Immunohistochemistry demonstrated robust L1CAM expression in adenomatoid tumors that was absent in normal mesothelial cells, malignant peritoneal mesotheliomas and multilocular peritoneal inclusion cysts. Together, these studies demonstrate that adenomatoid tumors of the male and female genital tract are genetically defined by TRAF7 mutation that drives aberrant NF-kB pathway activation
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PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS
Abstract
BACKGROUND
Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component.
METHODS
We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway.
RESULTS
The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia.
CONCLUSION
Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation
Homozygous Deletion of Six Olfactory Receptor Genes in a Subset of Individuals with Beta-Thalassemia
Progress in the functional studies of human olfactory receptors has been largely hampered by the lack of a reliable experimental model system. Although transgenic approaches in mice could characterize the function of individual olfactory receptors, the presence of over 300 functional genes in the human genome becomes a daunting task. Thus, the characterization of individuals with a genetic susceptibility to altered olfaction coupled with the absence of particular olfactory receptor genes will allow phenotype/genotype correlations and vindicate the function of specific olfactory receptors with their cognate ligands. We characterized a 118 kb β-globin deletion and found that its 3′ end breakpoint extends to the neighboring olfactory receptor region downstream of the β-globin gene cluster. This deletion encompasses six contiguous olfactory receptor genes (OR51V1, OR52Z1, OR51A1P, OR52A1, OR52A5, and OR52A4) all of which are expressed in the brain. Topology analysis of the encoded proteins from these olfactory receptor genes revealed that OR52Z1, OR52A1, OR52A5, and OR52A4 are predicted to be functional receptors as they display integral characteristics of G-proteins coupled receptors. Individuals homozygous for the 118 kb β-globin deletion are afflicted with β-thalassemia due to a homozygous deletion of the β-globin gene and have no alleles for the above mentioned olfactory receptors genes. This is the first example of a homozygous deletion of olfactory receptor genes in human. Although altered olfaction remains to be ascertained in these individuals, such a study can be carried out in β-thalassemia patients from Malaysia, Indonesia and the Philippines where this mutation is common. Furthermore, OR52A1 contains a γ-globin enhancer, which was previously shown to confer continuous expression of the fetal γ-globin genes. Thus, the hypothesis that β-thalassemia individuals, who are homozygous for the 118 kb deletion, may also have an exacerbation of their anemia due to the deletion of two copies of the γ-globin enhancer element is worthy of consideration
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Recurrent non-canonical histone H3 mutations in spinal cord diffuse gliomas.
The effect of ω-fatty acids on mrna expression level of PPARγ in patients with gastric adenocarcinoma
Background: The antineoplastic role of peroxisome proliferator-activated receptor gamma (PPARγ) ligandshas previously been demonstrated in several gastric cancer cell lines. Activation of PPARγ by polyunsaturated fatty acids (PUFAs) inhibits growth and proliferationof tumor cells. In this double-blind clinical study, we evaluate the effect of PUFAs on PPARγ mRNA expression in patients with gastric adenocarcinoma. Materials and Methods: A total of 34 chemotherapy-naive patients diagnosed with gastric adenocarcinoma were enrolled in the present study. According to treatment strategies, all subjects were divided into two groups, the first group (17 individuals) received cisplatin without supplements and the second group (17 individuals) received cisplatin plus orally administered PUFAs supplements for 3 weeks. The gastric biopsy samples were obtained from all participants before and after treatment, and PPARγ mRNA expression levels were evaluated by quantitative real-time polymerase chain reaction using validated reference genes. Results: Our findings revealed that PPARγ mRNA expression is significantly upregulated in group II afterreceiving cisplatin plus orally administered PUFAs supplements for three weeks (p < 0.0001), whereas PPARγ mRNA expression did not show significant alteration in group I after receiving cisplatin alone. Conclusion: The results of the study evidence that PPARγ may act as a potential target for the therapy of human gastric adenocarcinoma
Homozygous Deletion of Six Olfactory Receptor Genes in a Subset of Individuals with Beta-Thalassemia
Analysis of the telomere length of subpopulations of primary human hematopoietic cells
Telomeres are structures at the ends of eukaryotic chromosomes; they protect the ends from degradation and end-to-end fusions. Mammalian telomeres consist of a tandem array of G-rich repeats, with a length of two to 12 kb in human somatic cells. Somatic cell telomere length shortens with each cell division, leading to senescence or apoptosis. Critically short telomeres can lead to genomic instability, thus in cells that divide continually, such as germ cells, telomere length is maintained by telomerase. In a rare autosomal dominant form of dyskeratosis congenita, patients carry a mutation in the RNA template of telomerase, resulting in half maximal telomerase activity. Patients with this genotype die of aplastic anemia, indicating that maintenance of telomere length is likely critical, and may be particularly important in hematopoietic stem cells. Telomere length can be measured by a quantitative fluorescence in situ hybridisation and flow cytometry based method (Flow- FISH). In the present study, this technique was used to measure telomere length in lymphocytes and in "candidate" stem cell populations isolated from eight cadaveric marrow samples from normal adults (aged 14 to 48 years). Telomere length analysis of B and T cells - two populations that undergo activation-induced telomerase up-regulation - revealed that CD20⁺ B cells in the bone marrow had longer telomeres than CD3⁺ T cells (p<0.002). The CD34⁺CD38⁻ populations from each of the eight donors also had longer telomeres than the T cell subsets. The telomerase activity in T lymphocyte populations thus appears insufficient to prevent telomere shortening during differentiation from the pluripotent stem cell. To compare telomere length in different subsets of primitive hematopoietic ceils, we analysed FACS-purified CD34⁺CD38⁻ and CD34⁺CD38⁺ populations. The CD34⁺CD38⁻ cells had significantly longer telomeres than the CD34⁺CD38⁺ cells (p<0.02, n=8). The Side Population (SP) cells identified by FACS as Hoechst 33342'° cells did not have significantly longer telomeres than the CD34⁺CD38⁻ population. In two donor samples, additional populations were sorted, and the data is consistent with the proposed hierarchical pattern of these cell populations, with CD34⁺CD38⁻ thought to have the greatest proliferative potential and the longest telomeres. This data supports the hypothesis that hematopoietic cells with the greatest proliferative potential will have the longest telomere length. It is still unclear if a hematopoietic cell population exists within the SP with "germ-line" or "fetal" length telomeres. While we cannot exclude that a small subset of more primitive cells capable of maintaining long telomere length exists within the sorted SP cells that were analysed, we conclude that telomere length declines in the majority of the primitive hematopoietic cells examined here.Medicine, Faculty ofMedical Genetics, Department ofGraduat
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Src-family and Syk Tyrosine Kinases are Required for Neutrophil Effector Responses to Infection and Inflammation
Leukocyte specific CD18-integrins are critical in mediating cell recruitment and activation during host defense responses to bacterial infection. The signaling pathways downstream of CD18-integrins are dependent on Src-family kinases, including Hck, Fgr and Lyn, as well as the spleen tyrosine kinase, Syk. In a model of pneumococcal meningitis, deficiency of Hck, Fgr and Lyn results in increased susceptibility, due in part to the reduced ability of deficient neutrophils to phagocytose the bacteria, and undergo respiratory burst. To further investigate the role integrin signaling plays in host defense, we examined the responses of Syk-deficient neutrophils to bacterial challenge with serum-opsonized Staphylococcus aureus and Escherichia coli. Syk-conditional knockout mice lacking this kinase specifically in myeloid cells or just neutrophils were also used to investigate host responses in vivo. Syk-deficient neutrophils manifested impaired exocytosis of secondary and tertiary granules, reduced cytokine release and very poor activation of the NADPH oxidase in response to serum-opsonized S. aureus and E. coli. These functional defects correlated with impaired activation of c-Cbl, Pyk2, Erk1/2 and p38 kinases. Bacterial phagocytosis, NET formation and killing were also reduced in Syk-deficient cells, with a more profound effect following S. aureus challenge. In vivo, loss of Syk in myeloid cells or specifically in neutrophils resulted in reduced clearance of S. aureus following subcutaneous or intra-peritoneal infection, despite normal recruitment of inflammatory cells. These results indicate that loss of Syk kinase-mediated integrin signaling impairs leukocyte activation, leading to reduced host defense responses
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Epithelioid Angiomyolipoma With Prominent Papillary Architecture Mimicking Renal Cell Carcinoma: A Case Report.
Renal epithelioid angiomyolipoma (EAML) (epithelioid PEComa of the kidney), is a rare subtype of renal angiomyolipoma with the potential for aggressive behavior and a known diagnostically challenging entity. We present a renal EAML with unusual papillary architecture and tumor cells with abundant eosinophilic cytoplasm and cherry-red nucleoli with perinucleolar halos, strongly mimicking a fumarate hydratase (FH) deficient renal cell carcinoma (RCC). We herein report our findings and discuss the morphologic, immunohistochemical, and molecular pitfalls to consider in the differential of EAML, including with FH-deficient RCC and more recently described entities: TFEB-amplified RCC and other renal tumors with alterations in TSC1/2. Novel findings in this tumor include papillary morphology and a novel telomerase reverse transcriptase promoter rearrangement, which has not been previously reported in EAML
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