379 research outputs found
Kidney: Renal cell carcinoma with t(6;11)(p21;q12) MALAT1/TFEB
Review on Renal cell carcinoma with t(6;11)(p21;q12) MALAT1/TFEB, with data on clinics, and the genes involved
Kidney: Renal cell carcinoma with t(X;17)(p11;q23) CLTC/TFE3
Review on Renal cell carcinoma with t(X;1)(p11;q21) PRCC/TFE3, with data on clinics, and the genes involv
Kidney: Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3
Review on Renal cell carcinoma with inv(X)(p11q12) NONO/TFE3, with data on clinics, and the genes involved
Clinical Characteristics of Patients with Malignant Pleural Mesothelioma Harboring Somatic BAP1 Mutations
IntroductionGenomic studies of malignant pleural mesothelioma (MPM) have recently identified frequent mutations in the BRCA-associated protein 1(BAP1) gene. In uveal melanoma and clear cell renal cell carcinoma, BAP1 mutations are associated with poor outcomes but their clinical significance in MPM is unknown. We therefore undertook this study to define the characteristics of patients whose MPM tumors harbor somatic BAP1 mutation and to examine the relationship between BAP1 mutation and survival.MethodsWe reviewed the charts of 121 patients with MPM tumors diagnosed between 1991 and 2009 tested for BAP1 mutation, and extracted the following information: age at diagnosis, sex, histology, stage, smoking status, asbestos exposure, family or personal history of malignancy, and treatment including surgery, chemotherapy, and radiation as well as survival status.ResultsTwenty-four of the 121 tumors (20%) harbored somatic BAP1 mutations. The percentage of current or former smokers among cases with BAP1 mutations was significantly higher than in BAP1 wild-type cases, (75% versus 42%; p = 0.006). However, the types of nucleotide substitutions in BAP1 did not suggest that this association was because of a causative role of smoking in BAP1 mutations. No other clinical feature was significantly different among those with and without BAP1 mutations in their MPM. There was also no difference in survival according to somatic BAP1 mutation status.ConclusionThere is no apparent distinct clinical phenotype for MPM with somatic BAP1 mutation. The significance of the more frequent history of smoking among patients with BAP1-mutated MPM warrants further study
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
Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes.
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology
Deep Sequencing Reveals a Novel miR-22 Regulatory Network with Therapeutic Potential in Rhabdomyosarcoma
Current therapeutic options for the pediatric cancer rhabdomyosarcoma (RMS) have not improved significantly, especially for metastatic RMS. In the present work, we performed a deep microRNA profiling of the three major human RMS subtypes, along with cell lines and normal muscle, to identify novel molecular circuits with therapeutic potential. The signature we determined could discriminate RMS from muscle, revealing a subset of muscle-enriched microRNA (myomiR), including miR-22 which was strongly underexpressed in tumors. miR-22 was physiologically induced during normal myogenic differentiation and was transcriptionally regulated by MyoD, confirming its identity as a myomiR. Once introduced into RMS cells, miR-22 decreased cell proliferation, anchorage-independent growth, invasiveness and promoted apoptosis. Moreover, restoring miR-22 expression blocked tumor growth and prevented tumor dissemination in vivo. Gene expression profiling analysis of miR-22-expressing cells suggested TACC1 and RAB5B as possible direct miR-22 targets. Accordingly, loss and gain of function experiments defined the biological relevance of these genes in RMS pathogenesis. Finally, we demonstrated the ability of miR-22 to intercept and overcome the intrinsic resistance to MEK inhibition based on ERBB3 upregulation. Overall our results identified a novel miR-22 regulatory network with critical therapeutic implications in RMS
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