Gene Summary

Gene:CHN1; chimerin 1
Summary:This gene encodes GTPase-activating protein for ras-related p21-rac and a phorbol ester receptor. It is predominantly expressed in neurons, and plays an important role in neuronal signal-transduction mechanisms. Mutations in this gene are associated with Duane's retraction syndrome 2 (DURS2). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 17 August, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: CHN1 (cancer-related)

Agaram NP, Zhang L, Sung YS, et al.
Extraskeletal myxoid chondrosarcoma with non-EWSR1-NR4A3 variant fusions correlate with rhabdoid phenotype and high-grade morphology.
Hum Pathol. 2014; 45(5):1084-91 [PubMed] Free Access to Full Article Related Publications
Extraskeletal myxoid chondrosarcomas (EMC) are rare soft tissue sarcomas with distinctive histology and uncertain histogenesis, characterized by Ewing sarcoma breakpoint region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3) fusion in 75% of the cases. A smaller proportion of cases show NR4A3 fused to other gene partners including TATA binding protein-associated factor 15 (TAF15), transcription factor 12 (TCF12), and TRK-fused gene (TFG). The impact of various gene fusions on morphology and outcome has not been previously evaluated. We investigated 26 consecutive EMCs and correlated the genetic findings with morphology and clinical outcome. There were 5 females and 21 males (median age, 49.5 years). Mean size of the tumors was 11 cm. Fluorescence in situ hybridization analysis showed EWSR1-NR4A3 gene fusion in 16 cases (62%), TAF15-NR4A3 gene fusion in 7 cases (27%), and TCF12-NR4A3 gene fusion in 1 case (4%). Two cases showed only NR4A3 gene rearrangements. Morphologically, most EWSR1-rearranged tumors (10/16) showed low cellularity, minimal cytologic atypia, and low mitotic counts. In contrast, 80% of EMCs with variant (non-EWSR1) NR4A3 gene fusions (TAF15, TCF12) had high-grade morphology with increased cellularity, proliferation, and cytologic atypia, showing a plasmacytoid/rhabdoid morphology in half the cases. Follow-up showed that only 1 of 16 patients with EWSR1-rearranged tumors died of disease, in contrast to 3 (43%) of 7 TAF15-rearranged tumors. In conclusion, EMCs with variant NR4A3 gene fusions show a higher incidence of rhabdoid phenotype, high-grade morphology, and a more aggressive outcome compared with the EWSR1-NR4A3 positive tumors. Furthermore, fluorescence in situ hybridization assay for NR4A3, along with EWSR1, may be an additional ancillary test to confirm diagnosis of EMCs.

Patel N, Arya M, Muneer A, et al.
Molecular aspects of upper tract urothelial carcinoma.
Urol Oncol. 2014; 32(1):28.e11-20 [PubMed] Related Publications
OBJECTIVES: Primary upper tract urothelial carcinoma (UTUC) is a relatively rare tumor with up to 60% of cases being muscle invasive at presentation. In this article we review the molecular biology of UTUC, an understanding of which may help to address some of the dilemmas surrounding the diagnosis and treatment of this disease and ultimately lead to the introduction of personalized treatment plans.
METHODS: The literature search on the molecular aspects of UTUC was performed using the National Library of Medicine database.
RESULTS: UTUC and urothelial carcinomas of the bladder share many common biological pathways. UTUC are more commonly associated with conditions such as Balkan Endemic Nephropathy and Hereditary Non Polyposis Colon Cancer (HNPCC), the molecular basis of which is now being understood. A large number of potential biomarkers have been studied to help identify robust prognostic markers in UTUC.
CONCLUSION: Advances in our understanding of the biology of UTUC is may in the future help to identify novel druggable targets, clinically applicable biomarkers and guide treatment of the rare but lethal condition.

Cai S, Zhou Y, Liu J, et al.
[Experimental study on human leukemia cell line K562 senescence induced by ginsenoside Rg1].
Zhongguo Zhong Yao Za Zhi. 2012; 37(16):2424-8 [PubMed] Related Publications
OBJECTIVE: To observe the effect and mechanism of ginsenoside Rg1 in inducing senescence human leukemia K562 cell line.
METHOD: Proliferation of K562 cell line induced by Rg1 was detected by MTT colorimetric test for the purpose to screen optimal active concentration and time (20 micromol x L(-1) , 48 h). Impact of Rg1 on cell cycle was analyzed using flow cytometry. The percentage of staining positive cells was detected by SA-beta-Gal staining. The expressions of senescence-related genes such as p16, p53, p21, Rb, were detected by RT-PCR and the changes in ultramicro-morphology were observed by transmission electron microscopy.
RESULT: Rg1 can significantly inhibit the proliferation of K562 cells in vitro and arrest the cells in G2/M phase. The percentage of positive cells stained by SA-beta-Gal was dramatically increased (P < 0.05) and the expression of cell senescence-related genes were up-regulated. The observation of ultrastructure showed that cell volume increase, heterochromatin condensation and fragmentation, mitochondrial volume increase, lysosomes increase in size and number.
CONCLUSION: Rg1 can induce the senescence of leukemia cell line K562 and play an important role in regulating p53-p21-Rb, p16-Rb cell signaling pathway.

Heckman CA, Demuth JG, Deters D, et al.
Relationship of p21-activated kinase (PAK) and filopodia to persistence and oncogenic transformation.
J Cell Physiol. 2009; 220(3):576-85 [PubMed] Related Publications
Previously, we found that oncogenically transformed cells had fewer filopodia and more large, p21-activated kinase (PAK)-dependent features than normal cells. These large protrusions (LPs) were increased in cells expressing RhoA(N19) with Cdc42-associated kinase (ACK). Here, we determine how GTPase-mediated mechanisms of focal contact (FC) regulation affect these protrusions. Constructs encoding various proteins were introduced into cells which were then studied by microscopy and computerized image processing and analysis. Constructs that prevented PAK recruitment by PAK-interacting exchange factor (PIX) or restricted PAK residence time on FCs decreased both protrusions. Thus, filopodia were also PAK-dependent. A comparison of FC distribution in cells expressing PAK in the presence or absence of PAK kinase inhibitor domain (KID) suggested that PAK enlarged FCs without affecting the prevalence of either protrusion. KID or Nck expression increased LPs but not filopodia. Nck failed to synergize with KID or ACK and RhoA(N19) in enhancing LPs. Nck and KID synergistically enhanced filopodia, possibly because Nck recruited PAK to FCs while KID prevented their dissociation by PAK-mediated autophosphorylation. Coexpression of Nck, ACK, and RhoA(N19) abrogated filopodia and replicated the transformed phenotype. Since Nck recruitment of PAK is implicated in persistence of directional movement, we studied the PAK-Nck interface. Filopodia were eliminated by the Nck PAK-binding domain and LPs by the PAK Nck-binding domain. The results suggested that filopodia formation has more stringent requirements than LP formation, and Nck and PAK are used differently in the protrusions. Loss of filopodia in transformed cells may reflect defective regulation of GTPase mechanisms.

Mavrogenis AF, Patapis P, Papaparaskeva KT, et al.
Extraskeletal myxoid chondrosarcoma of the perineum.
Orthopedics. 2009; 32(3):216 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma is an aggressive tumor with significant metastatic potential. A 40-year-old man presented with an asymptomatic mass at the left ischial fossa. Magnetic resonance imaging showed a 9x6-cm mass with variable signal intensity and cystic formations. A computed tomography scan of the chest showed multiple pulmonary nodules. A computed tomography-guided core needle biopsy was consistent with low-grade extraskeletal myxoid chondrosarcoma. Despite the presence of lung metastases, wide resection of the primary tumor was performed. Wide resection included the perineal mass and the adjacent ischiopubic ramus. Postoperative recovery was uneventful. One month postoperatively, thoracotomy was performed, and approximately 20 pulmonary nodules were excised. Histological analysis of the excised specimens was consistent with extraskeletal myxoid chondrosarcoma metastases. Two years postoperatively, the patient is alive without evidence of local recurrence or distant disease. Extraskeletal myxoid chondrosarcoma is an unusual soft tissue sarcoma with ultrastructural and molecular features distinct from that of skeletal myxoid chondrosarcoma. The EWS-CHN gene fusion is highly specific to extraskeletal myxoid chondrosarcoma; the gene fusion is positive in >or=75% of cases. Treatment should include wide excision for local tumor control. Resection of the lung metastases is feasible. Because of the prolonged survival of patients with extraskeletal myxoid chondrosarcoma, long-term follow-up is recommended for early detection of local recurrence or distant metastases.

Barry JS, Reddy MA
The association of an epibulbar dermoid and Duane syndrome in a patient with a SALL1 mutation (Townes-Brocks Syndrome).
Ophthalmic Genet. 2008; 29(4):177-80 [PubMed] Related Publications
INTRODUCTION: Townes-Brocks Syndrome (TBS) is an autosomal dominant condition characterized by renal, anal, ear and thumb anomalies caused by SALL1 mutations. Ocular manifestations reported have included congenital cataracts, unilateral microphthalmia, optic nerve atrophy, and unilateral visual loss with bilateral Brushfield Spots. Iris and chorioretinal colobomata were described in one individual whose daughter had Duane syndrome.
METHODS: We present a case of TBS with a proven SALL1 mutation associated with unique ophthalmic features.
CASE REPORT: The first child of healthy unrelated parents was born after an uncomplicated pregnancy with multiple features consistent with TBS. The patient was heterozygous for a pathogenic SALL1 gene mutation c826C > T (pR276X). The child had an epibulbar dermoid and left Type 1 Duane syndrome. He also had tearing when he ate food (crocodile tears).
DISCUSSION: This case adds to the current knowledge of ophthalmic associations with SALL1 mutations; features characteristic of SALL1 mutations and others more commonly associated with SALL4 mutations (2) (epibulbar dermoid and Duane) being present. Truncated SALL1 protein alters the localization of full length SALL4 providing a theoretical mechanism for these associations, alternatively SALL1 mutations cause associated eye problems more directly. The possibility of chance association cannot be excluded. Our case is only the second we have found with a SALL1 mutation and TBS with Duane syndrome and the first to also have an epibulbar dermoid. The mutation present is that most commonly associated with TBS.
CONCLUSION: This case increases the demand to examine all children TBS for ophthalmic abnormalities.

Sanz-Moreno V, Gadea G, Ahn J, et al.
Rac activation and inactivation control plasticity of tumor cell movement.
Cell. 2008; 135(3):510-23 [PubMed] Related Publications
Tumor cells exhibit two different modes of individual cell movement. Mesenchymal-type movement is characterized by an elongated cellular morphology and requires extracellular proteolysis. In amoeboid movement, cells have a rounded morphology, are less dependent on proteases, and require high Rho-kinase signaling to drive elevated levels of actomyosin contractility. These two modes of cell movement are interconvertible. We show that mesenchymal-type movement in melanoma cells is driven by activation of the GTPase Rac through a complex containing NEDD9, a recently identified melanoma metastasis gene, and DOCK3, a Rac guanine nucleotide exchange factor. Rac signals through WAVE2 to direct mesenchymal movement and suppress amoeboid movement through decreasing actomyosin contractility. Conversely, in amoeboid movement, Rho-kinase signaling activates a Rac GAP, ARHGAP22, that suppresses mesenchymal movement by inactivating Rac. We demonstrate tight interplay between Rho and Rac in determining different modes of tumor cell movement, revealing how tumor cells switch between different modes of movement.

Escobar Alvarez Y, Khosravi Shahi P, Encinas García S, Izarzugaza Perón Y
[Effectivity of cetuximab monotherapy in the treatment of refractory advanced cancer of the head and neck].
An Med Interna. 2008; 25(4):159-62 [PubMed] Related Publications
INTRODUCTION: More than 90% of carcinoma of the head and neck (CHN) have an overexpression of the EGFR gene, and that overexpression is associated with a worse prognosis. Cetuximab is a monoclonal antibody against EGFR.
PATIENTS AND METHODS: We have conducted a retrospective study of 10 consecutive cases with metastatic and/or recurrent CHN treated with cetuximab monotherapy as second line therapy, with the main objective of analyzing the progression-free survival (PFS); we also analyzed the response rate, the overall survival (OS), and toxicity profile as second end points.
RESULTS: The median age was 55 years, and 100% of patients were males. Fourty percent of the patients received cetuximab as second line, and 60% as third line therapy. With a median follow-up of 13.5 months, the median PFS was 4 months (95%CI: 3.4-4.6 months), with a median OS of 9.7 months (95%CI: 2.9-16.6 months).The objective response rate was 10%, and the disease control rate was 60% (Partial response = 10% and stable disease for > 16 weeks = 50%). Thirty percent of patients had grade 3 rash.
CONCLUSIONS: Cetuximab monotherapy has a modest effectivity in the treatment of refractory CHN, but with a limited toxicity. Future studies should use combinations of cetuximab with others effective chemotherapeutic drugs in the treatment of CHN, such as taxanes.

Wang WL, Mayordomo E, Czerniak BA, et al.
Fluorescence in situ hybridization is a useful ancillary diagnostic tool for extraskeletal myxoid chondrosarcoma.
Mod Pathol. 2008; 21(11):1303-10 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumor characterized by a nodular growth pattern with eosinophilic cells usually in a reticular pattern and abundant myxoid stroma. In contrast to other myxoid sarcomas, the majority of extraskeletal myxoid chondrosarcomas harbor a balanced translocation, t(9;22)(q22;q12), that fuses EWSR1 with NR4A3 (also known as CHN). Other less common translocations involving NR4A3 have also been described. We examined the diagnostic utility of fluorescence in situ hybridization for extraskeletal myxoid chondrosarcoma using the LSI EWSR1 break-apart probe (Abbott Molecular/Vysis, Des Plaines, IL, USA). Sixteen cases of extraskeletal myxoid chondrosarcoma with formalin-fixed paraffin-embedded tissue available were retrieved (1991-2007). The mean age at time of presentation was 57 years (range, 30-78). The male to female ratio was 7:1. All cases where either consistent with or highly suggestive of the diagnosis, with most of the primary tumors occurring in the thigh, inguinal or gluteal region. Fifteen of 16 cases were analyzable, of which 14 (93%) were positive for the rearrangement of the EWSR1 locus. In this study, the vast majority of extraskeletal myxoid chondrosarcomas are associated with a rearrangement at the EWSR1 locus (22q12). Fluorescence in situ hybridization is useful to support the diagnosis of extraskeletal myxoid chondrosarcomas and may help to differentiate it from mimics such as other myxoid sarcomas, particularly in limited biopsies.

Chow WA
Update on chondrosarcomas.
Curr Opin Oncol. 2007; 19(4):371-6 [PubMed] Related Publications
PURPOSE OF REVIEW: This paper reviews recent molecular, biologic, developmental therapeutic, and clinical findings in conventional and variant chondrosarcomas.
RECENT FINDINGS: The prognosis of chondrosarcomas traditionally correlates with histologic grade and adequacy of surgery. Newer markers of cell differentiation, activation, genetics, and cell signaling may offer important prognostic information. Translational research has validated platelet-derived growth factor receptor, estrogen signaling, matrix metalloproteinase-1, histone deacetylase, methylthioadenosine phosphorylase, and vascular endothelial growth factor-A as potential therapeutic targets. Bisphosphonates may also possess important antitumoral effects. Molecular studies have established that extraskeletal myxoid chondrosarcoma is a unique entity defined by the presence of a fusion gene between the orphan nuclear receptor, CHN/NOR1, and a promiscuous partner, most commonly EWSR1. Clinical studies have shown that development of second malignancies is an uncommon but real risk for chondrosarcoma survivors; the benefit of chemotherapy for dedifferentiated chondrosarcomas remains questionable; and late recurrences of clear cell chondrosarcomas emphasize the need for long-term follow up.
SUMMARY: Chondrosarcomas are a heterogeneous group of bone and soft tissue tumors. Recent advances in molecular diagnostics, pathobiology, and developmental therapeutics will aid both scientists and clinicians in improving the classification and therapy of this diverse family of cartilaginous tumors.

Cheng CL, Chen KJ, Shih PH, et al.
Chronic renal failure rats are highly sensitive to aristolochic acids, which are nephrotoxic and carcinogenic agents.
Cancer Lett. 2006; 232(2):236-42 [PubMed] Related Publications
Aristolochic acid (AA), a component of some Chinese herbal medicines, may cause Chinese Herbs Nephropathy (CHN) and multi-systemic tumors by the formation of AA-DNA adducts. In this study, we established an animal model to further characterize the mechanisms of AA-induced diseases. Our results indicated that AA significantly inhibited rat growth in terms of weight gain. By measuring the serum creatinine levels, AA resulted in considerable damage to the rat renal system, not only for those in which chronic renal failure (CRF) was induced but also for normal healthy rats. Mutation-specific polymerase chain reaction (PCR) and XbaI restriction fragment length polymorphism (RFLP) revealed the CAA-->CTA transversion mutation at codon 61 of the H-ras proto-oncogene from the stomach tissues of CRF rats fed with AA, but not from other tissues of rats in the same experimental group. In addition, no such mutations were found in the tissues of CRF rats without AA treatment or healthy rats fed with AA. Our results strongly demonstrated that AA was in fact nephrotoxic and carcinogenic, especially to those CRF rats.

Tateishi U, Hasegawa T, Nojima T, et al.
MRI features of extraskeletal myxoid chondrosarcoma.
Skeletal Radiol. 2006; 35(1):27-33 [PubMed] Related Publications
OBJECTIVE: To describe the MRI features of extraskeletal myxoid chondrosarcoma in comparison with clinicopathologic findings.
DESIGN AND PATIENTS: The study comprised 12 male subjects and seven female subjects with a mean age of 53 years (range 16-76 years). MRI findings, evaluated by two radiologists with agreement by consensus, were compared for histopathologic features.
RESULTS: The tumor size ranged from 2.0 cm to 20.0 cm (mean 8.9 cm). Fusion gene transcripts could be detected in 13 (68%) of the 19 cases: EWS-CHN in nine cases, TAF2N-CHN in three, and TFG-TCH in one. There were six fusion-negative cases. Signal characteristics on T1-weighted and T2-weighted MR images were non-specific with regard to each cytogenetic variant. Peripheral enhancement was seen more frequently in tumors with the EWS-CHN variant than in those with other cytogenetic variants. The characteristic pattern of enhancement corresponded to the presence of fibrous septa and peripheral areas of high cellularity within lobules, by correlation with pathologic findings. All cases with TAF2N-CHN or TFG-TCH variants showed invasion of extracompartmental structure, bone, or vessels.
CONCLUSION: Extraskeletal myxoid chondrosarcoma is an uncommon soft-tissue malignancy that may be recognized by MRI features of multi-lobular soft-tissue mass often invading extracompartmental, bony, and vascular structures.

Hisaoka M, Ishida T, Imamura T, Hashimoto H
TFG is a novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma.
Genes Chromosomes Cancer. 2004; 40(4):325-8 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma (EMC) is characterized by recurrent chromosomal translocations resulting in fusions of the nuclear receptor gene NOR1 (also known as CHN or TEC) to various N-terminal partners, including EWS and TAF2N (or RBP56). Significant structural homology of EWS or TAF2N to TLS (or FUS) prompted us to investigate a potential novel gene fusion of NOR1 to TLS in EMCs without detectable known NOR1 fusions. In one of the EMCs examined, our reverse-transcription polymerase chain reaction using NOR1 and TLS primers unexpectedly amplified a cDNA sequence derived not from a TLS/NOR1 fusion but from a TFG/NOR1 fusion, a hitherto undescribed fusion type in EMC, probably a result of incidental misannealing by the TLS primer, which has a sequence partially identical to TFG. Encoding a protein with a putative coiled-coil structure, TFG previously was identified by a homology search in the Expressed Sequence Tag Database as having an SPYGQ-rich region similar to the N-terminal parts of EWS and TLS. TFG/NOR1 fusion appears to play an oncogenic role equivalent to those of other NOR1 fusions in EMC.

Sandberg AA
Genetics of chondrosarcoma and related tumors.
Curr Opin Oncol. 2004; 16(4):342-54 [PubMed] Related Publications
PURPOSE OF REVIEW: The burgeoning body of information on the genetic changes present in and underlying the development and biology of human cancers has carried implications regarding the possible genetic events that are responsible for not only the genesis of these cancers but also the hope of the cure for these cancers. Chondrosarcomas are a group of tumors that fall into this category. The purpose of this review is to summarize the genetic findings in these tumors.
RECENT FINDINGS: The histopathologic variability of chondrosarcomas is reflected in the complexity and lack of specificity of their cytogenetic and molecular genetic findings, except for extraskeletal myxoid chondrosarcomas. These are characterized in the preponderant number of cases by a translocation, t(9;22)(q22;q12), and in a small number of cases by variant translocations t(9;17)(q22;q11) and t(9;15)(q22;q21). These translocations lead to the formation of abnormal fusion genes and gene products (proteins). In each of these translocations, the CHN gene is involved, resulting in the chimeric fusion genes EWS/CHN, RBP56/CHN, and TCF12/CHN, respectively. The specific translocations and their associated molecular genetic changes are diagnostic of extraskeletal myxoid chondrosarcomas. The abnormal proteins resulting from these fusion genes aberrantly affect gene transcription and cellular signaling pathways thought to be responsible for initiating sarcoma formation. In skeletal (central) chondrosarcomas of varying histopathologic types, the cytogenetic and molecular genetic findings are variable, complex, and apparently lacking in specificity. These changes may reflect a stepwise process (or processes) of oncogenesis involving an array of genes.
SUMMARY: Although some cartilaginous tumors are characterized by specific or recurrent chromosome alterations and molecular genetic changes, much is yet to be learned about the nature and sequence of these genetics events and about their unique role in the stepwise process involved in the development and biology of each tumor type, both malignant and nonmalignant. Until such time, some of the genetic changes, particularly the presence of specific translocations, can be of definite diagnostic value.

Panagopoulos I, Mertens F, Isaksson M, et al.
Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma.
Genes Chromosomes Cancer. 2002; 35(4):340-52 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma (EMC) is a soft-tissue neoplasm cytogenetically characterized by the translocations t(9;22)(q22;q11-12) or t(9;17)(q22;q11), generating EWS/CHN or RBP56/CHN fusion genes, respectively. In the present study, 18 EMCs were studied both cytogenetically and at the molecular level. Chromosomal aberrations were detected in 16 samples: 13 with involvement of 9q22 and 22q11-12, and three with rearrangements of 9q22 and 17q11. Fifteen cases had an EWS/CHN fusion transcript and three had an RBP56/CHN transcript. The most frequent EWS/CHN transcript (type 1; 10 tumors), involved fusion of EWS exon 12 with CHN exon 3, and the second most common (type 5; two cases) was fusion of EWS exon 13 with CHN exon 3. In all tumors with RBP56/CHN fusion, exon 6 of RBP56 was fused to exon 3 of CHN. By genomic XL PCR and sequence analyses, the breakpoints from 14 cases were mapped in the EWS, RBP56, and CHN genes. In CHN, 12 breakpoints were found in intron 2 and only two in intron 1. In EWS, the breaks occurred in introns 7 (one break), 12 (eight breaks), and 13 (one break), and in RBP56 in intron 6. Repetitive elements such as Alu and LINE sequences seem to have limited, if any, importance in the genesis of EWS/CHN and RBP56/CHN chimeras. Furthermore, there were no chi, chi-like, topoisomerase II, or translin consensus sequences in the introns harboring the translocation breakpoints, nor could the number of topo I sites in EWS, RBP56, and CHN introns explain the uneven distribution of the breakpoints among EWS or CHN introns. Additional genetic events, such as nucleotide insertions, homologies at the junction, deletions, duplications, and inversions, were found to accompany the translocations, indicating that the chromosomal translocations do not require sequence-specific recombinases or extensive homology between the recombined sequences.

Okamoto S, Hara K, Sumita S, et al.
Extraskeletal myxoid chondrosarcoma arising in the finger.
Skeletal Radiol. 2002; 31(5):296-300 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma (EMCS) is a rare soft tissue sarcoma and usually occurs in deep soft tissues, especially of the proximal extremities and limb girdles. We present an unusual case of the tumor arising in the finger. The diagnosis was confirmed by molecular detection of a characteristic EWS-CHN/TEC fusion gene transcript. Molecular detection of the tumor specific fusion gene could be a valuable aid for the final diagnosis of EMCS, particularly in cases with unusual clinicopathological features.

Okamoto S, Hisaoka M, Ishida T, et al.
Extraskeletal myxoid chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 18 cases.
Hum Pathol. 2001; 32(10):1116-24 [PubMed] Related Publications
Extraskeletal myxoid chondrosarcoma (EMCS) is an uncommon clinicopathologically well-defined tumor, but its pathogenesis and biologic behavior are poorly understood. We reviewed 18 cases of EMCS to verify clinicopathologic features and immunohistochemical profiles together with molecular detection of the tumor-specific fusion genes. The tumors were located mainly in the proximal extremities and limb girdles (72%). Two tumors arose at unusual anatomic sites: the finger and the hip joint. Nine of the 17 followed-up patients were alive and disease free, 4 were alive with recurrences and/or metastases, and 4 died of the tumor. Fifteen tumors showed typical features of EMCS, and 3 had hypercellular areas in addition to conventional EMCS areas. The tumors were variably immunoreactive for S-100 protein (50%), NSE (89%), peripherin (60%), and synaptophysin (22%). Chromogranin A and some epithelial markers (AE1/AE3, CAM5.2, and epithelial membrane antigen) were entirely negative. Frequent expressions of the neural/neuroendocrine markers suggest possible neural/neuroendocrine differentiation in at least some EMCSs, in addition to chondroid differentiation. In a reverse-transcription polymerase chain reaction (RT-PCR) assay using paraffin-embedded specimens, EWS-CHN or TAF2N-CHN fusion gene transcripts characteristic of EMCS could be detected in 15 (83%) of the 18 cases: EWS-CHN type 1 in 11 cases, EWS-CHN type 2 in 1, and TAF2N-CHN in 3. Three fusion-negative cases included 2 conventional EMCSs and 1 considered a "cellular" variant of the tumor. None of 30 other soft tissue and bone tumors with myxoid or chondroid morphology that we examined contained these fusion genes. Thus, RT-PCR detection of EWS-CHN or TAF2N-CHN fusion gene using archival paraffin-embedded tissue is a feasible and useful ancillary technique for the diagnosis of EMCS.

Arlt VM, Schmeiser HH, Pfeifer GP
Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR.
Carcinogenesis. 2001; 22(1):133-40 [PubMed] Related Publications
The carcinogenic plant extract aristolochic acid (AA) is thought to be the major causative agent in the development of urothelial carcinomas found in patients with Chinese herb nephropathy (CHN). These carcinomas are associated with overexpression of p53, suggesting that the p53 gene is mutated in CHN-associated urothelial malignancy. To investigate the relation between AA-DNA adduct formation and possible p53 mutations, we mapped the distribution of DNA adducts formed by the two main components of AA, aristolochic acid I (AAI) and aristolochic acid II (AAII) at single nucleotide resolution in exons 5-8 of the human p53 gene in genomic DNA. To this end, an adduct-specific polymerase arrest assay combined with a terminal transferase-dependent PCR (TD-PCR) was used to amplify DNA fragments. AAI and AAII were reacted with human mammary carcinoma (MCF-7) DNA in vitro and the major DNA adducts formed were identified by the (32)P-postlabeling method. These adducted DNAs were used as templates for TD-PCR. Sites at which DNA polymerase progress along the template was blocked were assumed to be at the nucleotide 3' to the adduct. Polymerase arrest spectra thus obtained showed a preference for reaction with purine bases in the human p53 gene for both activated compounds. For both AAs, adduct distribution was not random; the strongest signals were seen at codons 156, 158-159 and 166-167 for exon 5, at codons 196, 198-199, 202, 209, 214-215 and 220 for exon 6, at codons 234-235, 236-237 and 248-249 for exon 7 and at codons 283-284 and 290-291 for exon 8. Overall guanines at CpG sites in the p53 gene that correspond to mutational hotspots observed in many human cancers seem not to be preferential targets for AAI or II. We compared the AA-DNA binding spectrum in the p53 gene with the p53 mutational spectrum of urothelial carcinomas found in the human mutation database. No particular pattern of polymerase arrest was found that predicts AA-specific mutational hotspots in urothelial tumors of the current p53 database. Thus, AA is not a likely cause of non-CHN-related urothelial tumors.

Harris M, Coyne J, Tariq M, et al.
Extraskeletal myxoid chondrosarcoma with neuroendocrine differentiation: a pathologic, cytogenetic, and molecular study of a case with a novel translocation t(9;17)(q22;q11.2).
Am J Surg Pathol. 2000; 24(7):1020-6 [PubMed] Related Publications
A case of extraskeletal myxoid chondrosarcoma (EMC) in which there was histochemical, immunohistochemical, and ultrastructural evidence of neuroendocrine differentiation is reported. Genetic investigations showed the recently described novel translocation t(9;17)(q22;q11.2) and associated fusion of the CHN and RBP56 genes, contrasting with the translocation t(9;22)(q22;q12) and EWS/CHN gene fusion found in the majority of EMCs.

Attwooll C, Tariq M, Harris M, et al.
Identification of a novel fusion gene involving hTAFII68 and CHN from a t(9;17)(q22;q11.2) translocation in an extraskeletal myxoid chondrosarcoma.
Oncogene. 1999; 18(52):7599-601 [PubMed] Related Publications
A proportion of extraskeletal myxoid chondrosarcomas (EMC) have been shown to have a characteristic translocation t(9;22)(q22;q12) involving the EWS gene at 22q12 and the CHN orphan nuclear receptor gene at 9q22. This translocation appears to be largely specific for EMC, but has not been detected in all such tumours. We report here a case of EMC with a t(9;17)(q22;q11.2) as the sole chromosome abnormality. We have determined that the translocation results in the fusion of the entire coding region of CHN to the N-terminal transactivation domain of RBP56/hTAFII68. This is the first report of a translocation involving RBP56/hTAFII 68, a protein with sequence homology to both EWS and TLS/FUS. The involvement of RBP56/hTAFII68 may explain some unusual features of the tumour.

Panagopoulos I, Mencinger M, Dietrich CU, et al.
Fusion of the RBP56 and CHN genes in extraskeletal myxoid chondrosarcomas with translocation t(9;17)(q22;q11).
Oncogene. 1999; 18(52):7594-8 [PubMed] Related Publications
Although most extraskeletal myxoid chondrosarcomas (EMC) are cytogenetically characterized by the translocation t(9;22)(q22;q12), another subset has recently been identified carrying a t(9;17)(q22;q11). Whereas the t(9;22) is known to result in fusion of the CHN (TEC) gene from 9q22 with the EWS gene from 22q12, creating a chimeric EWS/CHN, the genes involved in the t(9;17) of EMC are unknown. We examined two EMC with t(9;17)(q22;q11) and found that the CHN gene was recombined with the RBP56 gene from 17q11 to generate a chimeric RBP56/CHN. RBP56 has not previously been shown to be involved in tumorigenesis but it encodes a putative RNA-binding protein similar to the EWS and FUS (TLS) proteins known to play a pathogenetic role in several sarcomas. The presence of the RBP56/CHN chimeric gene in EMC with t(9;17)(q22;q11) shows that the N-terminal parts of EWS and RBP56 have similar oncogenic potential making them pathogenetically equivalent in oncoproteins arising from fusions with certain transcription factors.

Rubin BP, Fletcher JA
Skeletal and extraskeletal myxoid chondrosarcoma: related or distinct tumors?
Adv Anat Pathol. 1999; 6(4):204-12 [PubMed] Related Publications
Skeletal myxoid chondrosarcoma is a histologic variant of conventional skeletal myxoid chondrosarcoma, whereas extraskeletal myxoid chondrosarcoma is a distinct entity characterized by a reciprocal t(9;22) translocation resulting in fusion of the EWS and CHN genes. Rarely, extraskeletal myxoid chondrosarcoma can occur in bone, and it is difficult to describe such tumors, unambiguously, using the present nomenclature. Designation as "chordoid sarcoma of bone" would distinguish these cases from conventional skeletal myxoid chondrosarcoma.

Cosyns JP, Jadoul M, Squifflet JP, et al.
Urothelial lesions in Chinese-herb nephropathy.
Am J Kidney Dis. 1999; 33(6):1011-7 [PubMed] Related Publications
Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.

Antonescu CR, Argani P, Erlandson RA, et al.
Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study.
Cancer. 1998; 83(8):1504-21 [PubMed] Related Publications
BACKGROUND: Skeletal myxoid chondrosarcoma (SMC) is considered to be either a typical chondrosarcoma with prominent myxoid alterations or an altogether unique malignant cartilage tumor. Extraskeletal myxoid chondrosarcoma (EMC) is a relatively rare but well-recognized neoplasm. It was initially thought to be a low grade sarcoma of cartilage derivation and was recently found, in most cases, to contain a reciprocal t(9;22), resulting in a fusion of the EWS and CHN genes. Are SMC and EMC the same entity arising in two different locations, or are they two separate entities? To the authors' knowledge, this study represents the first systematic attempt to answer this question.
METHODS: Forty consecutive cases of EMC (20 cases) and SMC (20 cases) were compared by light and electron microscopy, immunohistochemistry, and molecular analysis. The mean clinical follow-up for both groups was 55 months. Histologic criteria for SMC consisted of 95% myxoid matrix, with only minimal hyaline cartilage formation.
RESULTS: The gender distribution was identical in both groups (13 males and 7 females). The mean age was 55 years for EMC patients and 45 years for SMC patients. The EMC tumors were predominantly located in the deep soft tissues of the lower extremity (60%) and buttock (20%), and the mean tumor size was 13 cm. SMC was most commonly located in the bones around the hip joint (pelvis 35%; proximal femur 20%) and shoulder (20%); the mean size was 9 cm. Histologic grade in the EMC group correlated with survival (82% of the high grade tumors metastasized). Electron microscopy performed in 8 EMC cases revealed intracisternal microtubules in 3 cases and prominent mitochondria in 5, whereas in 5 SMC cases it revealed only inconspicuous organelles. Molecular analysis for the EWS-CHN fusion RNA resulting from the t(9;22) was performed in 15 cases (9 EMC and 6 SMC) and was detected in 7 of 9 EMC cases and 0 of 6 SMC cases. In one case, the molecular structure of the EWS-CHN fusion RNA was novel. The probability of metastasis was significantly higher (P=0.004) for the EMC group than for the SMC group.
CONCLUSIONS: Although similar light microscopic features are noted in EMC and SMC, fundamental differences are noted at the ultrastructural and molecular levels, suggesting that EMC and SMC represent two distinct entities in the chondrosarcoma family of tumors.

Hibshoosh H, Lattes R
Immunohistochemical and molecular genetic approaches to soft tissue tumor diagnosis: a primer.
Semin Oncol. 1997; 24(5):515-25 [PubMed] Related Publications
During the past two decades we have witnessed the identification of an expanding list of immunohistochemical and molecular markers linked to histopathologically defined subtypes of tumors. These markers offer new insights and approaches to the classification of tumors with important prognostic and/or therapeutic implications. We review the potentially diagnostic immunohistochemical and molecular markers of soft tissue tumors (STTs). The immunohistochemical markers reviewed include vimentin, cytokeratin, desmin, HHF35, S100, myoD1, alpha1-antitrypsin, vascular markers (factor VIII, CD31, CD34), MIC2, and others. The potentially diagnostic chromosomal translocations and associated genes identified in STT include Ewing's/PNET t(11;22)(q24;q12)(FLI1;EWS), t(21;22)(q22;q12)(ERG; EWS); t(7;22)(p22;q12)(ETV1;EWS); desmoplastic small round cell tumor t(11;22)(p13;q12)(WT1;EWS); extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) (TEC(CHN);EWS); malignant ectomesenchymoma t(11;22)(q24;q12)(FLI1;EWS); alveolar rhabdomyosarcoma t(2;13)(q35;q14)(PAX-3;FKHR); t(1;13) (p36;q14)(PAX-7;FKHR); myxoid and round cell liposarcoma t(12;16)(q13;p11)(CHOP;TLS(FUS)); synovial sarcoma t(X;18)(p11;q11)(SSX1&2;SYT), and others. The nature, utility, and limitations of these markers in diagnostic settings are explored.

Brody RI, Ueda T, Hamelin A, et al.
Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma.
Am J Pathol. 1997; 150(3):1049-58 [PubMed] Free Access to Full Article Related Publications
The pathogenesis of myxoid chondrosarcoma (CS) is poorly understood. A recurrent translocation, t(9;22) (q22;q12), has been recognized in CS, specifically in extraskeletal myxoid CS. Recently, this translocation has been shown to represent a rearrangement of the EWS gene at 22q12 with a novel gene at 9q22 designated CHN (or TEC). Sequence analysis suggests that CHN encodes a novel orphan nuclear receptor with a zinc finger DNA-binding domain. The structure of this gene fusion has been characterized in only a limited number of extraskeletal myxoid CSs and its presence in other types of CS has not been extensively examined. We studied 46 cases of CS (8 extraskeletal myxoid, 4 skeletal myxoid, 4 mesenchymal, and 30 other) for the EWS/CHN gene fusion by reverse transcriptase polymerase chain reaction, Southern blotting, and long-range DNA polymerase chain reaction. The EWS/CHN gene fusion was present in 6 of 8 extraskeletal myxoid CSs and was not detected in any of the remaining cases, including the 4 skeletal myxoid CSs. The negative findings in the latter cases suggest that skeletal myxoid CS is pathogenetically distinct from its extraskeletal counterpart. Notably, 2 cases of extraskeletal myxoid CS showed neither an EWS/CHN fusion transcript nor EWS/CHN genomic fusion nor EWS or CHN genomic rearrangement, suggesting genetic heterogeneity within extraskeletal myxoid CS. Finally, we also provide evidence for alternative splicing of the 3' end of the fusion transcript. Extraskeletal myxoid CS thus represents yet another sarcoma type containing a gene fusion involving EWS.

Clark J, Benjamin H, Gill S, et al.
Fusion of the EWS gene to CHN, a member of the steroid/thyroid receptor gene superfamily, in a human myxoid chondrosarcoma.
Oncogene. 1996; 12(2):229-35 [PubMed] Related Publications
The specific chromosomal translocation t(9;22)(q22-31;q11-12) has been observed in the myxoid variant of human chondrosarcoma. In agreement with this observation we report that the EWS gene located at chromosome band 22q12 becomes fused to CHN, a member of the steroid/thyroid receptor gene superfamily located at 9q22-31, in a skeletal myxoid chondrosarcoma. CHN appears to be the human homologue of the rat gene NOR1, which was recently identified as a sequence overexpressed in rat brain cells undergoing apoptosis. Our results also indicate that the chimaeric EWS-CHN gene encodes a EWS-CHN fusion protein in which the C-terminal RNA-binding domain of EWS is replaced by the entire CHN protein, comprising a long N-terminal domain, a central DNA binding domain and a C-terminal ligand-binding/dimerisation domain.

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