Cyclin Alterations in Giant Cell Tumor of Bone

Abstract

Cyclins play an important role in regulating the passage of dividing cells through critical checkpoints in the cell cycle. Because alterations of several cyclins, especially cyclin D1, have been implicated in the development of many human neoplasms, we examined 32 cases of giant cell tumor of long bones for cyclin D1 gene amplification and protein overexpression using differential polymerase chain reaction and immunohistochemistry, respectively. In addition, the expression of cyclin D3, cyclin B1, and the proliferation-associated antigen Ki-67 (MIB-1) was assessed immunohistochemically. Low-level cyclin D1 gene amplification was detected in 61% of giant cell tumor cases. All tumors showed cyclin D1, cyclin D3, cyclin B1, and Ki-67 (MIB-1) staining; however, the distribution was very characteristic. Cyclin D1 protein expression was seen predominantly in the nuclei of the giant cells, with occasional mononuclear cells staining. There was no correlation between cyclin D1 gene amplification and protein overexpression. Cyclin D3 staining showed a similar distribution, with 88% of cases showing protein overexpression. Cyclin D1 and/or D3 staining in the giant cells was never associated with staining for either cyclin B1 or Ki-67 (MIB-1), as the expression of the latter two proteins was restricted to the mononuclear cells. Cyclin B1 overexpression was seen in 44% of cases. Ki-67 (MIB-1) staining was present in all cases, and between 10 to 50% of the mononuclear cells were positive. These results suggest that alterations in cyclin D1 and/or D3 might play a role in the pathogenesis of giant cell tumor of bone. Alterations of several cell cycle regulatory proteins, especially those involved in the G1-to-S transition, such as D-type cyclins, are detected in many human tumors. Genes encoding D-type cyclins (D1, D2, and D3) are induced by mitogenic stimuli (1) and, together with their catalytic partners CDK4 and CDK6, phosphorylate the retinoblastoma protein (pRb) (2) and allow cells to cross the G1/S restriction point. The cells then become committed to DNA replication and completion of the cell cycle (3). Because D-type cyclins provide the link between mitogenic signals and activation of the cell cycle (1, 4) and because of their regulatory function in the G1-to-S transition (5), constitutive activation of the D-cyclin pathway can reduce or overcome certain mitogen requirements for cell proliferation (6) and thereby contribute to oncogenic transformation (7-9). Although studies suggest that overexpression of cyclin D1 appears to be insufficient on its own to transform primary cells, it may cooperate with other oncogenes to induce transformation (10 -13). Amplification of the cyclin D1 gene and/or overexpression of the protein are observed in a number of human malignancies, such as certain types of epithelial cancers, lymphomas, and some central nervous system tumors (14). Benign and premalignant lesions of the breast (15) and epithelial dysplasias of the oral and laryngeal mucosa (16, 17) also show cyclin D1 alterations, s...

Prognostic value of p53 protein expression in giant cell tumor of bone

“…The percentage of cells expressing cellular staining with the immunohistochemical stain for Ki-67 gives the proliferative index. The index is usually high in aggressive tumors and is regarded as a poor prognostic factor [25,26,27]. In our series, giant cells were Ki-67-negative in all cases and mononuclear cells were Ki-67-positive in various proportions of tumor cells.…”

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

“…In this regard, it is noteworthy that the association between cyclin D3 and proliferation is likely to be tumor-specific, since it has been previously reported in different types of NHL with the exception of mantle cell lymphoma, 17,34 in pancreatic adenocarcinoma, 38 melanoma 39 and oral dysplastic mucosa, 40 but not in breast carcinoma, 18 gastrointestinal stromal tumor 41 and giant cell tumor of bone. 42 Grade III FLs are biologically distinct from grade I/II FLs 13 and behave aggressively, thus requiring the same therapies as diffuse large B-cell lymphomas (DLBCLs). Accordingly, the prevalence of cyclin D3 IR in grade III FLs in our series is similar to that reported in DLBCLs.…”

Giant cell tumor of bone express p63

“…2 In previous studies we observed that the giant cell component of these tumors overexpressed cyclin D1 protein. 3 Compared to the mononuclear component, the giant cells also had higher levels of p21 and more p21 bound to cyclin D1. 4 p21 may explain the cyclin D1 accumulation, but the mechanism leading to increased p21 expression is unknown.…”