Loss of p16^INK4a expression correlates with decreased survival in Pediatric osteosarcomas

Abnormalities of the G₁ cell-cycle checkpoint are commonly reported in cancers at various anatomic sites. pRB, p16^INK4a and cyclin D1 are critical G₁-checkpoint proteins responsible for maintaining the balance of cellular proliferation. We examined a series of 38 pediatric osteosarcomas for abnormal expression of pRB, p16^INK4a and cyclin D1 by immunohistochemical analysis of archival biopsy specimens. Overall, 17/38 (45%) osteosarcomas showed evidence of G₁-checkpoint abrogation, including 11/38 (29%) with loss of pRB expression and 6/38 (16%) with loss of p16^INK4a expression. Cyclin D1 over-expression was not detected. There was an inverse correlation between loss of pRB and p16^INK4a expression (p = 0.07). pRB and p16^INK4a abnormalities were independent of site of disease, presence of metastasis at diagnosis and percentage of tumor necrosis in the resection specimen. Clinical follow-up was available on all patients (median 31.6 months, range 5.9-116 months). Absence of p16^INK4a expression significantly correlated with decreased survival in univariate analysis (p = 0.03), while loss of pRB expression did not affect survival. Immunohistochemical analysis of p16^INK4a expression in pediatric osteosarcomas may be a useful adjunctive marker of prognosis.