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Neuro Oncol. 2015 Jan;17(1):63-9. doi: 10.1093/neuonc/nou140. Epub 2014 Jul 19.

Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis.

Author information

1
Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).

Abstract

BACKGROUND:

Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive disease with no evidence of effect from adjuvant therapy. It is further associated with the hereditary syndrome neurofibromatosis type 1 (NF1). Silencing of the tumor suppressor gene RASSF1A through DNA promoter hypermethylation is known to be involved in cancer development, but its impact in MPNSTs remains unsettled.

METHODS:

The RASSF1A promoter was analyzed by methylation-specific PCR in 113 specimens, including 44 NF1-associated MPNSTs, 47 sporadic MPNSTs, 21 benign neurofibromas, and 1 nonneoplastic nerve sheath control.

RESULTS:

RASSF1A methylation was found only in the malignant samples (60%) and identified a subgroup among patients with NF1-associated MPNST with a poor prognosis. These patients had a mean 5-year disease-specific survival of 27.3 months (95% CI: 17.2-37.4) versus 47.4 months (95% CI: 37.5-57.2) for NF1 patients with unmethylated promoters, P = 0.014. In multivariate Cox regression analysis, methylated RASSF1A remained an adverse prognostic factor independent of clinical risk factors, P = .013 (hazard ratio: 5.2; 95% CI: 1.4-19.4).

CONCLUSION:

A considerable number of MPNST samples display hypermethylation of the RASSF1A gene promoter, and for these tumors, this is the first molecular marker that if validated can characterize a subgroup of patients with inferior prognosis, restricted to individuals with NF1.

KEYWORDS:

MPNST; NF1; RASSF1A; methylation; survival

PMID:
25038505
PMCID:
PMC4416132
DOI:
10.1093/neuonc/nou140
[Indexed for MEDLINE]
Free PMC Article

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