Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1261473 (sarcoma)
 25,952 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ewing Sarcoma is an important tumor of bone and soft tissue. The SNPs Arg72Pro of TP53 and T309G of MDM2 have been associated with many cancer types and have been differently distributed among populations worldwide. Based on a case-control design, this study aimed to assess the role of these SNPs in 24 Ewing Sarcoma patients, compared to 91 control individuals. DNA samples were extracted from blood and genotyped for both SNPs by PCR-RFLP and confirmed by DNA sequencing. The results showed an association between the G allele of the T309G and Ewing Sarcoma (P=0.02). Comparing to the TT carriers, the risk of G allele carriers was 3.35 (95% CI=1.22-9.21) with P=0.02. At the genotypic level, an association of the TT genotype with the control group (P=0.03) was found. Comparing to the TT genotype, the risk of TG and GG was 2.97 (95% CI=1.03-8.58) with P=0.04 and 5.00 (95% CI=1.23-20.34) with P=0.02, respectively. No associations regarding the Arg72Pro SNP were found. Considering that the T309G has been associated with several types of cancer, including sarcomas, our results indicate that this SNP may also be important to Ewing Sarcoma predisposition.
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PMID:Ewing Sarcoma: influence of TP53 Arg72Pro and MDM2 T309G SNPs. 2366 Oct 19

Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed.
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PMID:Novel pathways and molecular targets for the treatment of sarcoma. 2366 Dec 64

Soft tissue sarcomas are rare and heterogeneous tumours. Histological diagnosis is often difficult because of the numerous types and subtypes reported and morphological similarities with benign lesions in certain cases. Molecular analyses performed in an appropriate clinical and histological context improve the patients' management in the case of sarcomas with simple genomic profile: the identification of a specific and objective molecular abnormality can confirm a diagnosis, rule out another one, provide prognostic information, and guide the selection of targeted therapy About 15% of sarcomas bear a specific translocation that can be identified by FISH or RT-PCR. The search for a MDM2 amplification, reflecting the presence of an amplicon in the 12q region, is a sensitive and specific tool for the diagnosis of atypical lipomatous tumors/well-differentiated liposarcomas and dedifferentiated iposarcomas. The presence and the type of KITor PDGFRA activating mutation guide the diagnosis and treatment of GIST. Certain molecular abnormalities are found in several tumour types, emphasizing the importance of integrating the results of any molecular study within the morphological and immunohistochemical context: In France, sarcoma diagnosis is structured around a reference network (RRePS) that provides every pathologist an access to these molecular analysis tools.
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PMID:[Soft tissue sarcomas: clinical application of molecular biology]. 2368 49

A rare sclerosing variant of rhabdomyosarcoma characterized by prominent hyalinization and pseudovascular pattern has recently been described as a subtype biologically distinct from embryonal, alveolar, and pleomorphic forms. We present cytogenetic and molecular findings as well as experimental studies of an unusual case of sclerosing rhabdomyosarcoma. The primary lesion arose within the plantar subcutaneous tissue of the left foot of an otherwise healthy 23-year-old male who eventually developed pulmonary nodules despite systemic chemotherapy. Two genetic abnormalities identified in surgical and/or autopsy samples of the tumor were introduced into 10T1/2 murine fibroblasts to determine whether these genetic changes cooperatively facilitated transformation and growth. Cytogenetic analysis revealed a complex abnormal hyperdiploid clone, and MDM2 gene amplification was confirmed by fluorescence in situ hybridization. Cancer gene mutation screening using a combination of multiplexed PCR and mass spectroscopy revealed a PIK3CA exon 20 H1047R mutation in the primary tumor, lung metastasis, and liver metastasis. However, this mutation was not cooperative with MDM2 overexpression in experimental assays for transformation or growth. Nevertheless, MDM2 and PIK3CA are genes worthy of further investigation in patients with sclerosing rhabdomyosarcoma and might be considered in the enrollment of these patients into clinical trials of targeted therapeutics.
Sarcoma 2013
PMID:MDM2 Amplification and PI3KCA Mutation in a Case of Sclerosing Rhabdomyosarcoma. 2376 66

Sarcomas are rare, heterogenous, and often difficult to classify. A large proportion of sarcomas are associated with specific molecular genetic lesions such as translocations, mutations, and amplifications, which are helpful in the diagnosis of individual cases. However, the exact impact of molecular genetics on the final diagnosis of sarcomas is unknown. In this study, all soft tissue and visceral sarcomas arising in patients living in 3 European regions in 2 countries (representing 13 million inhabitants) were collected and reviewed during 2 consecutive years. A molecular analysis was performed for all suspicions of sarcomas with specific genetic lesions [mutations of KIT/PDGFRA in gastrointestinal stromal tumors (GISTs), reciprocal translocation, or amplification of MDM2 in atypical lipomatous tumors, well-differentiated liposarcoma-dedifferentiated liposarcoma (ALT/WDLPS-DDLPS)]. To evaluate the impact of molecular tests, a premolecular analysis diagnosis was proposed with 3 categories of certainty: certain, probable, or possible. A molecular analysis was performed in 763/1484 tumors corresponding to 295 cases in which GIST was suspected, 248 sarcomas with a suspicion of translocation, and 220 cases in which ALT/WDLPS-DDLPS was suspected. Molecular analysis was found to be useful (confirms a probable diagnosis) in 11 (4%) GISTs, 62 (26%) suspicions of translocation, and 66 (31%) suspicions of ALT/WDLPS-DDLPS; and necessary (allows a possible diagnosis) in 2 (<1%) GISTs, 31 (12%) suspicions of translocation, and 19 (9%) suspicions of ALT/WDLPS-DDLPS. This study performed in an epidemiological setting demonstrates the significant impact of molecular analysis on the final sarcoma diagnosis and favors such an analysis on any tumor with a suspicion of a specific genomic abnormality and for which the diagnosis is uncertain.
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PMID:Impact of molecular analysis on the final sarcoma diagnosis: a study on 763 cases collected during a European epidemiological study. 2377 73

We report a rare case of recurrent retroperitoneal dedifferentiated liposarcoma with osteosarcomatous components. An 82-year-old male diagnosed with recurrent retroperitoneal liposarcoma underwent a tumor resection. Histologically, osseous matrix with osteoid and mature hyaline cartilaginous tissues with high cellularity were observed in a fibrous background through most of the tumor, and scattered MDM2- and CDK4-positive atypical hyperchromatic stromal cells were detected surrounding the dedifferentiated areas. Dedifferentiation occurs in up to 10% of well-differentiated liposarcomas, frequently resembling a malignant fibrous histiocytoma-like pleomorphic sarcoma. In contrast, divergent differentiation with osteosarcomatous components is considered to be extremely rare.
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PMID:Retroperitoneal dedifferentiated liposarcoma with osteosarcomatous components: a case report. 2382 26

Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of ring chromosomes. Such structures are mitotically unstable and during tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many ring-containing tumors remains poorly characterized. Ring chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization (FISH), global genomic copy number and gene expression data on ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of ring chromosome: MDM2-positive and MDM2-negative rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative rings commonly show complete loss of either CDKN2A or RB1 -both known to be important for genome integrity. Sarcomas with MDM2-positive rings instead show co-amplification of a variety of potential driver oncogenes. More than 100 different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets.
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PMID:Integrative genome and transcriptome analyses reveal two distinct types of ring chromosome in soft tissue sarcomas. 2407 Aug 70

The purpose of this study is to report the author's experience with 32 cases of pleomorphic liposarcoma to further broaden the clinicopathological spectrum. The tumours occurred equally in males and females with ages ranging from 11 to 83 years (median, 56 years). Tumour site included the extremities (17 cases), abdomen/retroperitoneum (4 cases), internal organs (5 cases), thoracic cavity/mediastinum (2 cases), orbit, neck, groin and scrotum (1 case each). The diagnostic pleomorphic lipoblasts were identified in 31 primary tumours and one recurrent tumor but varied widely in proportion between cases or different areas of the same tumor. Four tumors contained sheets or focal aggregates of lipoblasts with epithelioid morphology. The nonlipogenic component in 26 cases had an appearance of undifferentiated pleomorphic sarcoma, whereas in six cases it was consistent with intermediate to high grade myxofibrosarcoma. The pleormorphic and epithelioid lipoblasts displayed variable expression of S100 protein. There was no signal of amplified MDM2 gene in 10 cases tested by fluorescence in situ hybridization. This study further illustrates that pleomorphic liposarcoma is a distinctive entity with no relationship to either well differentiated liposarcoma or dedifferentiated liposarcoma. Albeit very rare, pleomorphic liposarcoma can occur in teenaged patients and internal organs.
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PMID:Pleomorphic liposarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic study of 32 additional cases. 2427 14

Nutlin-3a is a small-molecule antagonist of p53/MDM2 that is being explored as a treatment for sarcoma. In this study, we examined the molecular mechanisms underlying the sensitivity of sarcomas to Nutlin-3a. In an ex vivo tissue explant system, we found that TP53 pathway alterations (TP53 status, MDM2/MDM4 genomic amplification/mRNA overexpression, MDM2 SNP309, and TP53 SNP72) did not confer apoptotic or cytostatic responses in sarcoma tissue biopsies (n = 24). Unexpectedly, MDM2 status did not predict Nutlin-3a sensitivity. RNA sequencing revealed that the global transcriptomic profiles of these sarcomas provided a more robust prediction of apoptotic responses to Nutlin-3a. Expression profiling revealed a subset of TP53 target genes that were transactivated specifically in sarcomas that were highly sensitive to Nutlin-3a. Of these target genes, the GADD45A promoter region was shown to be hypermethylated in 82% of wild-type TP53 sarcomas that did not respond to Nutlin-3a, thereby providing mechanistic insight into the innate ability of sarcomas to resist apoptotic death following Nutlin-3a treatment. Collectively, our findings argue that the existing benchmark biomarker for MDM2 antagonist efficacy (MDM2 amplification) should not be used to predict outcome but rather global gene expression profiles and epigenetic status of sarcomas dictate their sensitivity to p53/MDM2 antagonists.
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PMID:Nutlin-3a efficacy in sarcoma predicted by transcriptomic and epigenetic profiling. 2433 67

p53 is one of the main regulators of apoptosis, senescence, cell cycle arrest and DNA repair. The expression, function and stabilization of p53 are governed by a complex network of regulators including p14(ARF) and MDM2. MDM2 is the main negative regulator of p53 activity and stability. Unlike tumours in adults, which tend to overcome p53 regulation by p53 mutations, the paediatric tumours neuroblastoma and sarcoma frequently retain wild type p53. Nevertheless, in childhood cancer the p53 pathway is commonly impaired due to upstream MDM2-p14(ARF)-p53 network aberrations. In contrast, aberrations of the p53 downstream pathway are very rare. In cancer cells with intact p53 downstream function MDM2 inhibition, and subsequent rapid increases in nuclear p53 levels, potently "re-activate" dormant apoptotic pathways and rapidly induce apoptotic cell death. As a result MDM2-p53 interaction inhibitors, including cis-imidazolines analogs (Nutlins), are potentially very effective agents in neuroblastoma and sarcomas. Predictive biomarkers are important as a lack of p53 mutations appears to reliably predict response to these inhibitors. Tumours should be screened for p53 mutations in children considered for MDM2-p53 interaction inhibitors. In addition, it is essential that other predictive biomarkers are investigated. The serum concentration of macrophage inhibitory cytokine- 1 (MIC-1) may be a good pharmacodynamic biomarker based on recent findings. In conclusion, targeting the interaction between p53 and its main negative regulator MDM2 represents a major new therapeutic approach in poor prognosis paediatric malignancies without p53 mutations.
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PMID:MDM2-p53 interaction in paediatric solid tumours: preclinical rationale, biomarkers and resistance. 2438 12


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