Identification of p53 as a strong predictor of survival for patients with malignant peripheral nerve sheath tumors

¹ Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
² Division of Cancer Medicine and Radiotherapy, Department of Oncology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
³ Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
⁴ Division of Pathology and Institute for Medical Informatics, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway
⁵ Department of Pathology, Lund University Hospital, Lund, Sweden
⁶ Department of Clinical Genetics, Lund University Hospital, Lund, Sweden
⁷ Department of Informatics, University of Oslo, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
⁸ Institute for Medical Informatics, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
⁹ Department of Molecular Biosciences, University of Oslo, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Montebello, NO-0310 Oslo, Norway

^* To whom correspondence should be addressed. E-mail: ragnhild.a.lothe{at}rr-research.no.

	Abstract

The purpose of this study was to identify new prognostic biomarkers with clinical impact in the cancer disease malignant peripheral nerve sheath tumor (MPNST), a highly aggressive malignancy for which no consensus therapy exists beside surgery. We have used tissue microarrays (TMA) to assess in situ expression of 14 cell cycle regulating proteins in 64 well-characterized MPNST patients; 36 sporadic and 28 with neurofibromatosis type 1 (NF1). A new software application was developed for evaluation and logistics of the TMA images, and a literature survey of cell cycle proteins in MPNST was done. For NF1-associated patients, there was a clear association between nuclear expression of p53 and poor survival (P = 0.004). Among the other proteins analyzed, we also found significant associations to survival and clinical variables, but not as strong as for p53. For the total series of MPNSTs, p53 was shown to be an independent predictor of survival, and patients without remission, tumor size larger than 8 cm, and positive p53 expression had 60 times higher risk of dying within the first 5 years compared to the remaining patients (P = 0.000002). This is the most comprehensive study on in situ protein expression in MPNST so far, and expressed p53 was found as a strong surrogate marker for outcome. Patients in complete remission with a primary p53 positive MPNST diagnosis may be considered a high risk subgroup and candidates for adjuvant treatment.

Key Words: cyclin D1, immunohistochemistry, MPNST, neurofibroma, NF1, p14^ARF, p53

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