Purpose: p14ARF, p15INK4b and p16INK4a are tumor suppressor genes that are located closely at 9p21 and are often co-inactivated by genetic or epigenetic alterations. Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with poor prognosis. However, the prognostic implications of inactivation of p14ARF, p15INK4b and p16INK4a in MPNSTs have not been adequately investigated. Here we performed a genetic, epigenetic and expression analysis of p14ARF, p15INK4b and p16INK4a, and clarified the prognostic significance of their inactivation in MPNSTs. Experimental Design: p14ARF, p15INK4b and p16INK4a protein expression were assessed by immunohistochemistry in 129 formalin-fixed samples of MPNST including 85 primary tumors. 39 samples, for which frozen material was available, were also investigated by western blotting and quantitative RT-PCR to detect p14ARF, p15INK4b and p16INK4a protein and mRNA expression, and by multiplex real-time PCR, PCR single strand conformation polymorphism and methylation-specific PCR to detect p14ARF, p15INK4b and p16INK4a gene alterations. Results: Immunohistochemically decreased expressions of p14ARF, p15INK4b and p16INK4a were observed in 48%, 54% and 49% of primary MPNSTs, respectively, and were significantly correlated with their concordant mRNA levels. As for gene alterations, homozygous deletion of CDKN2A was detected in one third of the cases. Inactivation of p14ARF and p16INK4a was associated with poor prognosis by both univariate and multivariate analyses. Furthermore, cases with inactivation of all p14ARF, p15INK4b and p16INK4a genes showed the worst prognosis in a combined prognostic assessment. Conclusion: A comprehensive analysis of p14ARF, p15INK4b and p16INK4a inactivation status provides useful prognostic information in MPNSTs.
- Received September 6, 2010.
- Revision received December 28, 2010.
- Accepted January 10, 2011.
- Copyright © 2011, American Association for Cancer Research.