Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that the cAMP responsive element-binding protein (CREB) may act as a transcription regulator of aromatase in breast cancer cells. However, there is little knowledge on the expression of CREB1 in human breast cancer and its clinical significance. The current study investigated the expression pattern of CREB1 in human breast cancer at the mRNA and protein level and correlated it with the clinical outcome. CREB1 staining was primarily seen in the nucleus of both normal and tumour cells. At the mRNA level, we found a significantly higher level of CREB1 in breast tumour tissues (n=120) as compared to non-neoplastic mammary tissues (n=33, p=0.0092). When compared between different histological types CREB1 expression was significantly higher in ductal carcinoma as compared to lobular and other breast carcinoma. Patients with a poor prognosis and with metastasis had a markedly raised level of CREB1 compared to patients who were disease free. In addition, node-positive tumours had higher levels of CREB1 than node-negative tumours (p=0.0018). Finally, patients with high levels of CREB1 had a significantly shorter disease-free survival [95.3 (68.4-122.3, 95% CI) months] compared with those with lower levels [133.9 (123.5-144.2) months, p=0.0193]. This study demonstrates that the level of CREB1 in breast cancer patients is elevated and is significantly raised in patients with a poor prognosis, metastatic disease and nodal involvement. We conclude that the level of CREB1 expression is aberrant in human breast cancer and is associated with disease progression in breast cancer patients.
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PMID:Expression of transcription factor CREB1 in human breast cancer and its correlation with prognosis. 1778 59

Clear cell sarcoma (CCS) of soft tissue is a rare sarcoma with morphologic similarities to malignant melanoma but a distinct genetic background including a chromosomal translocation, t(12;22)(q13;q12), or a resultant EWSR1-ATF1 fusion gene. In addition, the tumors occurring in the gastrointestinal tract may have a variant fusion gene EWSR1-CREB1. This study analyzed the clinicopathologic and molecular genetic features of 33 CCSs of soft tissue. The patients' ages ranged from 13 to 73 years (median, 30 y), and there was a male predominance (20 males, 13 females). The tumors were located in the deep soft tissues of the extremities (N=25) or in the trunk or limb girdles (N=8). The median tumor size was 4 cm (range, 1 to 15 cm). The tumor cells were either spindle or epithelioid, and they were arranged predominantly in a short fascicular (N=19) or a solid sheetlike growth pattern (N=14). Minor histologic variations included the existence of rhabdoid cells (N=8), bizarre pleomorphic cells (N=6), alveolar structures due to loss of cellular cohesion (N=3), and a seminomalike pattern (N=2). Tumor necrosis was evident in 14 tumors, and the mitotic activity ranged from 0 to 43 mitotic figures (MF)/10 high-power fields (HPF) (mean: 4 MF/10 HPF). Immunohistochemically, the tumors were consistently positive for S-100 protein (33/33) and variably or focally for HMB45 (32/33), microphthalmia transcription factor (26/32), Melan A (23/32), CD57 (25/33), bcl-2 (30/32), synaptophysin (14/32), CD56 (7/32), epithelial membrane antigen (12/33), cytokeratin (AE1/AE3) (1/32), CD34 (3/32), c-erbB-2 (10/32), c-kit (5/32), and c-met (5/32). alpha-Smooth muscle actin, desmin, and cytokeratin (CAM5.2) were negative. Reverse transcription-polymerase chain reaction using RNA extracted from formalin-fixed, paraffin-embedded tissues demonstrated transcripts of the EWSR1-ATF1 (31/33) or EWSR1-CREB1 fusion gene (2/33). In 26 cases with available clinical information, local recurrences and metastases developed in 2 and 15 patients, respectively. Ten patients were dead of the disease, and the overall survival rate was 63% at 5 years. However, no clinicopathologic or molecular variables associated with the patients' prognosis were identified. This study confirms that CCS is an aggressive soft tissue tumor with a melanocytic phenotype and wider morphologic variations than had been generally considered. In cases with unusual histologic findings, molecular detection of the EWSR1-ATF1/CREB1 fusion genes provides critical information regarding the diagnosis of the tumor.
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PMID:Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. 1830 Aug 4

Clear cell sarcoma (CCS) of tendons and aponeuroses/malignant melanoma (MM) of soft parts is a rare tumor and in the majority of cases presents a characteristic reciprocal translocation t(12;22)(q13;q12) that results in fusion of the EWS and ATF1 genes. Although the melanocytic differentiation of CCS is indisputable, its precise lineage remains unclear. Typically, the slowly growing tumor affects the extremities of adolescents or young adults, especially around the ankle and foot. CCS is classically regarded as a deep soft tissue tumor associated with tendons or aponeuroses. This traditional view is put into perspective by the description of primary CCS of the gastrointestinal tract that may have a variant fusion gene EWSR1-CREB1. We describe 12 cases of cutaneous CCS and discuss the differential diagnoses. These 12 cases share an identical immunohistochemical profile with MM and thus can easily be confused with a dermal variant of spindle cell MM or metastasis of MM. The patients' ages ranged from 6 to 74 years (median: 25 y), and there was a female predominance (10 females, 2 males). Most tumors (n = 9) were located on the extremities, 2 tumors arose on the back, and 1 on the abdomen. The mean tumor size was 0.97 cm (range, 0.4 to 1.7 cm). Six cases showed invasion of the subcutis, the other 6 cases were entirely dermal. Tumor necrosis was evident in 2 cases, melanin pigment in 2 cases, and ulceration in 1 tumor. All cases showed uniform nests and fascicles of pale spindled or slightly epitheloid cells with finely granular eosinophilic or clear cytoplasm. There was fair pleomorphism with plump spindled nuclei and significantly prominent nucleoli. Multinucleated wreath-like tumor giant cells were observed in two-thirds of cases, but were usually present only focally. The dense cellular aggregates were encased by delicate fibrous septa. The stroma showed a sclerotic reticulated pattern. Partly, the nests of spindle cells bordered the epidermis, prima vista mimicking junctional nests of melanocytes. The specific translocation pattern was confirmed in all cases by fluorescence in situ hybridization. Local recurrences and metastases developed in 2 and 3 patients, respectively, and 1 patient died of the disease.
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PMID:Cutaneous clear cell sarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 12 cases emphasizing its distinction from dermal melanoma. 2008 59

Angiomatoid fibrous histiocytoma is a rare soft tissue tumor of intermediate biologic potential, predominantly arising in superficial extremities of children and young adults. Less than 5% metastasize. We describe a case of angiomatoid fibrous histiocytoma in the scalp of an 8-year-old boy, which metastasized to a postauricular lymph node 3 years after primary tumor excision. Histologically, primary and metastasis comprised nodules of bland ovoid cells, with primary additionally showing hemorrhagic cavities, fibrous capsule, and lymphoplasmacytic inflammation. Both strongly expressed desmin, with focal epithelial membrane antigen. Reverse transcription-polymerase chain reaction showed EWSR1-CREB1 fusion transcripts in both primary and metastasis. This is, to our knowledge, the first description of genetically proven metastatic angiomatoid fibrous histiocytoma. Angiomatoid fibrous histiocytoma can mimic both benign and malignant lesions, and although most behave indolently, it is important to recognize their metastatic potential.
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PMID:Metastatic angiomatoid fibrous histiocytoma of the scalp, with EWSR1-CREB1 gene fusions in primary tumor and nodal metastasis. 2319 25

Cutaneous myoepithelial tumors demonstrate heterogenous morphologic and immunophenotypic features. We previously described, in brief, 7 cases of cutaneous myoepithelioma showing solid syncytial growth of ovoid, spindled, or histiocytoid cells. We now present the clinicopathologic features in a series of 38 cases of this distinctive syncytial variant, which were diagnosed between 1997 and 2012 (mostly seen in consultation). There were 27 men and 11 women, with a median age of 39 years (range, 2 mo to 74 y). Primary anatomic sites were the upper extremity (11, including 2 on the hand), upper limb girdle (3), lower extremity (14; 3 on the foot), back (6), face (2), chest (1), and buttock (1); the typical presentation was as either a polypoid or papular lesion. Tumors were well circumscribed and centered in the dermis and ranged in size from 0.3 to 2.7 cm (median 0.8 cm). Microscopically all tumors showed a solid sheet-like growth of uniformly sized ovoid to spindled or histiocytoid cells with palely eosinophilic syncytial cytoplasm. Nuclei were vesicular with fine chromatin and small or inconspicuous nucleoli and exhibited minimal to no atypia. Mitoses ranged from 0 to 4 per 10 HPF; 28 tumors showed no mitoses. Necrosis and lymphovascular invasion were consistently absent. Adipocytic metaplasia, appearing as superficial fat entrapped within the tumor, was seen in 12 cases. Chondro-osseous differentiation was seen in 1 tumor. All tumors examined were diffusely positive for EMA, and the majority showed diffuse staining for S-100 protein (5 showing focal staining). Keratin staining was focal in 1 of 33 tumors and seen in rare cells in 3 other cases. There was also positivity for GFAP (14/33), SMA (9/13), and p63 (6/11). Most lesions were treated by local excision. The majority of tumors tested (14/17; 82%) were positive by fluorescence in situ hybridization for EWSR1 gene rearrangement; testing for potential fusion partners (PBX1, ZNF444, POU5F1, DUX4, ATF1, CREB1, NR4A3, DDIT3, and NFATc2) was negative in all EWSR1-rearranged tumors. No FUS gene rearrangement was detected in 2 tumors lacking EWSR1 rearrangement. Follow-up information is available for 21 patients (mean follow-up 15 mo). One patient with a positive deep margin developed a local recurrence 51 months after initial biopsy. All other patients with available follow-up information, including 11 who had positive deep margins, are alive with no evidence of disease and no reported metastases. In summary, cutaneous syncytial myoepithelioma is a morphologically distinct variant that more frequently affects men, occurs over a wide age range, and usually presents on the extremities. Tumors are positive for S-100 protein and EMA, and, unlike most myoepithelial neoplasms, keratin staining is infrequent. EWSR1 gene rearrangement is present in nearly all tumors tested and likely involves a novel fusion partner. Prior reports describe some risk of recurrence and metastasis for cutaneous myoepithelial tumors; however, the syncytial variant appears to behave in a benign manner and only rarely recurs locally.
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PMID:Cutaneous syncytial myoepithelioma: clinicopathologic characterization in a series of 38 cases. 2358 65

Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm arising within the wall of the small bowel, stomach, or large bowel, predominantly in children and young adults. It is an aggressive tumor with a high rate of local recurrence, metastases, and early death from disease. Histologically, it is composed of relatively monomorphic ovoid or round cells with clear to eosinophilic cytoplasm, arranged in sheets and sometimes papillary or alveolar architectures, often with CD68-positive osteoclast-like giant cells in variable numbers, and is associated with EWSR1-CREB1 gene fusions. Its pathogenesis is unknown, and histologically it can be easily confused with a variety of intra-abdominal neoplasms. We describe a case of CCSLGT with molecular characterization, presenting as an acutely obstructing small bowel mass in a 33-year-old male, which occurred as a second malignant neoplasm 20 years after treatment with surgery, radiotherapy, and cisplatin and doxorubicin chemotherapy for childhood hepatoblastoma. This gives further insight into the clinical setting of this highly aggressive neoplasm and highlights the use of radiation therapy as a possible etiologic factor.
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PMID:Clear cell sarcoma-like tumor of the gastrointestinal tract, presenting as a second malignancy after childhood hepatoblastoma. 2471 28

Clear cell sarcoma-like tumor of the gastrointestinal tract (CCSLGT) is a rare malignant neoplasm that occurs in the wall of the small bowel, stomach, or large bowel, predominantly in young adults. It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. Clear cell sarcoma-like tumor of the gastrointestinal tract is positive for S100 protein, invariably negative for melanocyte-specific markers and is often also positive for neuroendocrine markers. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions. Here, we discuss the current status of CCSLGT, including histologic, immunophenotypic, and molecular findings.
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PMID:Clear cell sarcoma-like tumor of the gastrointestinal tract: an evolving entity. 2572 38

Very recently a new designation of "Malignant Neuroectodermal Gastrointestinal Tumor" has been proposed for an aggressive form of neuroectodermal tumor with features similar to that of Clear Cell Sarcoma of Soft Tissue, however without a melanocytic differentiation. Also known as "clear cell sarcoma-like tumors of the gastrointestinal tract", these tumors show some features strongly suggesting an origin from a gastrointestinal neuroectodermal precursor cell unable to differentiate along the melanocytic lineage. They occur mainly in young and middle-aged adults, and have a poor prognosis with a high rate of liver and lymphnode metastases. Histologically they are composed of epithelioid or oval-to spindle cells with a sheet-like or nested pattern of growth, strongly positive for neural markers (S-100, SOX10, and vimentin) and negative for the melanocytic ones. EWSR1 gene rearrangements including EWSR1-ATF1 or EWSR1-CREB1 GENE fusions are typically assessed in these tumors. Here we report a case of malignant neuroectodermal gastrointestinal tumor which immunophenotypically unusually expressed FLI-1, occurring in a 29-year-old man with a previous medical history of Ewing sarcoma. We finally suggest that this case might be a further evidence of a link between these two entities.
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PMID:An unusual association of malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like) and Ewing sarcoma. 2616 85

Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.
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PMID:Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion. 2776 30

Tumor metastasis is the main reason of cancer-related death for gastric cancer (GC) patients and gene expression microarray data indicate that kinesin family member 26B (KIF26B) is one of the most upregulated genes in metastatic GC samples. Specifically, KIF26B expression was upregulated in a stepwise manner from non-tumorous gastric mucosa, primary GC tissues without metastasis, via primary GC tissues with metastasis, to secondary lymph node metastatic (LNM) foci. Increased expression of KIF26B was correlated with tumor size, positive LNM or distant metastases and poor prognosis. KIF26B, negatively regulated by miR-372, promoted GC cell proliferation and metastasis in vitro and in vivo. Mechanistic investigations confirmed that the main target of KIF26B was the vascular endothelial growth factor (VEGF) signaling pathway, particularly by inhibition or overexpression of VEGFA, PXN, FAK, PIK3CA, BCL2 and CREB1. Thus, KIF26B, a novel oncogene regulated by miR-372, promotes proliferation and metastasis through the VEGF pathway in GC.
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PMID:KIF26B, a novel oncogene, promotes proliferation and metastasis by activating the VEGF pathway in gastric cancer. 2858 13


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