Malignant Transformation of Neurofibromas in Neurofibromatosis 1 Is Associated with CDKN2A/p16 Inactivation

• Published in: The American journal of pathology Vol. 155; no. 6; pp. 1879 - 1884
• Main Authors: Nielsen, Gunnlaugur P., Stemmer-Rachamimov, Anat O., Ino, Yasushi, Møller, Michael B., Rosenberg, Andrew E., Louis, David N.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.12.1999; ASIP; American Society for Investigative Pathology
• Subjects: Adolescent; Adult; Aged; Biological and medical sciences; Cell Transformation, Neoplastic - genetics; Child; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; DNA Methylation; Female; Gene Deletion; Genes, p16; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; Neurofibroma - genetics; Neurofibroma - metabolism; Neurofibroma - pathology; Neurofibromatosis 1 - genetics; Neurofibromatosis 1 - metabolism; Neurofibromatosis 1 - pathology; Neurology; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Regular; Tumors of the nervous system. Phacomatoses; Human; Immunohistochemistry; Skin disease; Nervous system diseases; Phacomatosis; Malignant tumor; Inactivation; CDKN2 gene; Neurofibromatosis Recklinghausen; Genetic disease; Polymerase chain reaction; Pathology; Malignant transformation; Tumor progression; Benign neoplasm; Molecular biology; Tumor suppressor gene; Neurofibroma
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)65507-1

Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We examined the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however, were essentially immunonegative for p16, with striking transitions in cases that contained both benign and malignant elements. None of the benign tumors had CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in MPNSTs did not reveal any abnormalities. These results show that malignant transformation of NF is associated with loss of p16 expression, which is often secondary to homozygous deletion of the CDKN2A/p16 gene. The findings suggest that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in NF1 patients and raises the possibility that p16 immunohistochemistry may provide ancillary information in the distinction of NF from MPNST.