Expression profile and molecular genetic regulation of cyclin D1 expression in epithelioid sarcoma

Abstract

Epithelioid sarcoma is a distinctive, aggressive soft tissue tumor typically presenting as a subcutaneous or deep dermal mass in the distal extremities of young adults. Molecular genetic data of well-characterized cases of epithelioid sarcoma are sparse. A recent cytogenetic study of epithelioid sarcoma by conventional metaphase comparative genomic hybridization reported recurrent gains at chromosome 11q13, a region containing many genes, including the cyclin D1 gene. Cyclin D1 is a positive cell cycle regulator that is overexpressed in a variety of neoplasms, including mantle cell lymphoma and breast carcinoma. The objective of this study was to examine cyclin D1 expression in epithelioid sarcoma. Of 24 cases evaluated, 23 (96%) displayed cyclin D1 nuclear expression using immunohistochemical evaluation. Eight cases, which expressed cyclin D1 by immunohistochemistry, were evaluated by fluorescence in situ hybridization (FISH) and RNA in situ hybridization (RISH) for amplification of the cyclin D1 gene and messenger RNA (mRNA) expression, respectively. Seven of eight cases showed a typical eusomic state. One case showed pseudoamplification due to aneusomy/polysomy. There was no evidence of cyclin D1 gene amplification or messenger RNA overexpression detected by FISH or RNA in situ hybridization analyses, respectively. Our data clearly demonstrate that cyclin D1 protein is upregulated in epithelioid sarcoma, suggesting a role for this cell cycle regulator in the pathogenesis of epithelioid sarcoma. The high level of cyclin D1 protein expression in epithelioid sarcoma appears to be regulated by translational and/or post-translational mechanisms. Keywords: cyclin D1 protein expression; epithelioid sarcoma; gene amplification; mRNA expression Epithelioid sarcoma is a rare, aggressive soft tissue tumor generally presenting as a subcutaneous or deep dermal mass in the upper extremities of adolescents and young adults, and has a high risk for local recurrence and metastasis. 1-3 Histologically, epithelioid sarcoma is characterized by nodular aggregates of cytologically malignant epithelioid and/or spindled cells, often with central necrosis. The tumor cells are immunoreactive for cytokeratin, epithelial membrane antigen, vimentin, and 50% of cases are immunoreactive for CD34. 4 Cytogenetic data for epithelioid sarcoma are relatively sparse. The abnormalities described include t(8;22)(q22;q11), allelic loss of 22q, gains at 1q, 6p, and 9q, and aberrations of 18q and 8q. 2 Recent cytogenetic data by conventional metaphase comparative genomic hybridization (CGH) have shown recurrent gains at 11q13, 5 a region with many genes, including the cyclin D1 gene. Cyclin D1, originally identified as a molecule that links growth factor signaling and cell cycle machinery, is a critical molecule in the regulation of progression through the G1 phase of the cell cycle, thereby promoting cell proliferation. [6][7][8] The cell cycle progression is tightly regulated by cell cycle regulatory molecules, including cyclins, cyclin-dependent k...

Cyclin D1 gene amplification in proliferating haemangioma

“…Numerical alterations of the cyclin D1 gene have been detected in various tumours. The gain of the cyclin D1 gene has been reported to be attributable to gene amplification and/or chromosome 11 polysomy, which influences the poorer prognosis and/or the more aggressive behaviour of the tumour Lin et al 2005;Yasui et al 2006;Pestell and Li 2006). Moreover, the expression of vascular endothelial growth factor (VEGF), which promotes endothelial cell proliferation and angiogenesis, has been reported to be decreased on cyclin D1 inhibition (Yasui et al 2006).…”

“…The overexpression of cyclin D1 may lead to premature cycling through the G 1 /S transition resulting in the propagation of unrepaired DNA damage, the accumulation of genetic errors and the selective growth advantage of the altered cells. The increase of cyclin D1 gene within tumours has been reported to be attributable to gene amplification and/or chromosome 11 polysomy and reflects poorer prognosis and/or more aggressive behaviour of the tumour Lin et al 2005). Accordingly, the present study has been conducted to evaluate the possible numerical alteration of the cyclin D1 gene in proliferating haemangiomas and its correlation with the natural course of proliferating haemangioma and the success of the commonly used non-excision modalities of haemangioma treatment.…”

“…The cyclin D1 (CCND1) gene located on 11q13 chromosome has proven to have a role in regulating the cell cycle and in promoting cell proliferation and angiogenesis. Numerical alterations of the cyclin D1 gene have been reported in a wide variety of neoplasms Lin et al 2005). Anti-angiogenic endostatin-induced G 1 arrest has been observed after the inhibition of the cyclin D1 gene in endothelial cells and upregulation of cyclin D1 gene seems to be associated with the proliferation of endothelial cells (Yasui et al 2006).…”

PPFIA1 and CCND1 are frequently coamplified in breast cancer

“…TMA sections were used for dual-color fluorescence in situ hybridization (FISH) analysis (Lin et al, 2005). A commercial kit was used for proteolytic slide pretreatment (paraffin pretreatment reagent kit; Vysis, Downers Grove, Illinois).…”

CyclinD1, a prominent prognostic marker for endometrial diseases

“…As a cell -cycle regulator, CyclinD1 is essential for progression through G1 phase and is a candidate proto-oncogene [5]. Mutations, amplification and over-expression of CCND1 gene, which can alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis [6-9]. …”