CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations.
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.
Nielsen
G P
GP
James Homer Wright Pathology Laboratories, Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA. gnielsen@partners.org
Burns
K L
KL
Rosenberg
A E
AE
Louis
D N
DN
D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism*; D002648:Child; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D016161:Genes, Retinoblastoma / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins
D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases