Nielsen G P, Burns K L, Rosenberg A E, Louis D N
James Homer Wright Pathology Laboratories, Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Am J Pathol. 1998 Jul;153(1):159-63. doi: 10.1016/S0002-9440(10)65556-3.
Osteosarcomas often suffer mutations of the RB (retinoblastoma) gene, with resultant inactivation of the pRb protein. pRb is one component in a cell-cycle control pathway that includes the p16 (encoded by the CDKN2A gene) and cyclin-dependent kinase 4 (cdk4, encoded by the CDK4 gene) proteins. We therefore sought to determine whether the CDKN2A and CDK4 genes were altered in those osteosarcomas that lacked RB inactivation. Twenty-one osteosarcomas (2 low-grade and 19 high-grade) were evaluated for homozygous deletion of the CDKN2A gene, CDK4 amplification, and allelic loss of the RB gene, as well as for expression of p16 and pRb proteins. Five high-grade osteosarcomas showed loss of p16 expression; four of these had homozygous CDKN2A deletions, and the fifth had a probable deletion obscured by numerous nonneoplastic, p16-immunopositive multinucleated giant cells. Thus, p16 immunohistochemistry may provide a sensitive means for assessing CDKN2A status. Twelve tumors (including the two low-grade osteosarcomas) were immunopositive for pRb, and nine tumors were immunonegative for pRb. Of the five cases with CDKN2A/p16 alterations, none had allelic loss of the RB gene and all expressed pRb, suggesting that each of these tumors had an intact RB gene. None of the tumors showed CDK4 amplification. No alterations were detected in the two low-grade osteosarcomas. This study suggests that CDKN2A is a tumor suppressor inactivated in osteosarcomas that lack RB mutations and that the p16-pRb cell-cycle control pathway is deregulated in a large number of high-grade osteosarcomas.
骨肉瘤常发生RB(视网膜母细胞瘤)基因突变,导致pRb蛋白失活。pRb是细胞周期控制通路的一个组成部分,该通路包括p16(由CDKN2A基因编码)和细胞周期蛋白依赖性激酶4(cdk4,由CDK4基因编码)蛋白。因此,我们试图确定在那些缺乏RB失活的骨肉瘤中,CDKN2A和CDK4基因是否发生改变。对21例骨肉瘤(2例低级别和19例高级别)进行了评估,检测CDKN2A基因的纯合缺失、CDK4扩增、RB基因的等位基因缺失,以及p16和pRb蛋白的表达。5例高级别骨肉瘤显示p16表达缺失;其中4例有CDKN2A基因的纯合缺失,第5例可能的缺失被大量非肿瘤性、p16免疫阳性的多核巨细胞掩盖。因此,p16免疫组化可能为评估CDKN2A状态提供一种敏感方法。12例肿瘤(包括2例低级别骨肉瘤)pRb免疫阳性,9例肿瘤pRb免疫阴性。在5例发生CDKN2A/p16改变的病例中,无一例有RB基因的等位基因缺失,且均表达pRb,提示这些肿瘤中的每一个都有完整的RB基因。所有肿瘤均未显示CDK4扩增。在2例低级别骨肉瘤中未检测到改变。本研究表明,CDKN2A是一种在缺乏RB突变的骨肉瘤中失活的肿瘤抑制基因,并且在大量高级别骨肉瘤中p16-pRb细胞周期控制通路失调。