Rb-loss is associated with high malignancy in chondrosarcoma

Abstract

Loss of function of the human retinoblastoma gene (Rb) is a frequent genetic abnormality in human malignancies and causes a disturbance in the cell cycle and loss of normal proliferation and differentiation. We studied the loss of heterozygosity (LOH) of the Rb gene in 31 formalin-fixed, paraffin-embedded cartilaginous tumors using polymerase chain reaction. The tumors were subdivided into 8 cases of dedifferentiated (DD) chondrosarcoma, 17 cases of conventional chondrosarcoma (nine grade 1, seven grade 2 and one grade 3), 4 enchondromas and 2 chondroblastomas. Both components of DD chondrosarcoma, the low-grade and anaplastic components, were separated by a microdissection approach. The genetic data were correlated with the expression of the Rb protein examined by Rb immunohistochemistry. We found Rb-LOH in one grade 3 chondrosarcoma, and in the anaplastic component in 7 of 8 cases of DD chondrosarcoma (89% of all high-grade chondrosarcomas). All tumors with Rb-LOH were immunohistochemically Rb-negative. The only case of DD chondrosarcoma negative for Rb-LOH in both components of the tumor also showed weak expression of the Rb protein in the anaplastic component. All benign cartilaginous tumors, low-grade chondrosarcomas and lowgrade tumor components of DD chondrosarcomas were negative regarding Rb-LOH but positive in Rb immunohistostaining. We concluded that Rb-LOH predominantly occurs in high-grade chondrosarcomas. However, it is not a marker for identifying low-grade tumors with a tendency towards progression or local recurrence.

Loss of heterozygosity for Rb locus and pRb immunostaining in laryngeal cancer: a clinicopathologic, molecular and immunohistochemical study.

“…The connection between Rb LOH and altered pRb expression was significant (p<0.01). Association between LOH on 13q where Rb locus is located, and the decreased pRb expression was observed in many tumours, such as lung, liver, bladder, oesophagus, endometrial cancer and chondrosarcoma [10,[19][20][21][22][23]. Our data suggest that LOH at Rb locus plays a role in the tumorigenesis of a subset of laryngeal cancers and correspond with the altered expression of the pRb.…”

“…The clinical relevance of pRb expression in human tumours is still controversial: low levels of this protein have been found to correlate with a worse prognosis in prostate, breast, endometrial, head and neck cancer but not in bladder and gastric cancers [10,19,20,[25][26][27][28]. In these data the loss of pRb protein was observed in 9/67 cases (13.4) and was significantly correlated with T status (p=0.03) and local recurrence (p=0.035).…”

The molecular pathogenesis of dedifferentiated chondrosarcoma

“…LOH of Rb is associated with decreased Rb expression and is significantly correlated with high malignancy in cartilaginous tumors. In addition, LOH of Rb has been found only in the anaplastic component 2535. Aberrant promoter methylation in the fragile histidine triad (FHIT) gene is seen only in highgrade dedifferentiated components.…”

“…Although FHIT is involved in the regulation of apoptosis and in cell cycle control, the molecular mechanism or functional pathway is still unknown. Irregularities in Rb, p53 and FHIT in the anaplastic component may be the key abnormalities in dedifferentiation of chondrosarcomas 11242535…”

Molecular oncogenesis of chondrosarcoma: impact for targeted treatment

“…Alterations resulting in over-activation of cyclin/CDK complexes or inactivation of CDKinhibiting proteins have been found in chondrosarcoma and disrupt the cell cycle and initiate uncontrolled cell proliferation. Deletion or low expression of the pRb gene was found in a large majority of all high-grade chondrosarcomas [63]. Also alterations in cyclin/CDK complexes and its inhibitors have been described.…”