title: CDKN2A mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature.
abstract: An inherited germline mutation in CDKN2A is the most common cause of familial atypical multiple mole melanoma (FAMMM) syndrome. Although it is well known that CDKN2A mutations confer an increased risk for melanoma and pancreatic carcinoma, the association with an increased risk for nerve sheath tumours and other tumour types is under-recognized. We report a family with a missense mutation (c.151-1G>C) at the acceptor splice site of intron 1 of CDKN2A, resulting in loss of function of both tumour suppressor proteins p16(INK) (4) and p14(ARF) . This mutation is associated with a clinical phenotype of FAMMM syndrome in which patients develop numerous benign and malignant mutations, brain tumours, sarcomas and other solid tumours, in addition to melanoma and dysplastic naevi. Our proband initially presented with multiple nerve sheath tumours, leading to diagnostic confusion with Neurofibromatosis type 1. Loss of p14 expression results in increased MDM2-mediated degradation of the tumour suppressor protein p53, and predisposes mutation carriers to multiple benign and malignant neoplasms. This article highlights the importance of considering CDKN2A mutations in patients with dysplastic naevi, melanoma and multiple nerve sheath tumours, specifically those with histological features of both neurofibromas and schwannomas. We also present a discussion of medical management for patients with this high-risk cancer susceptibility syndrome.
authors.affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, GA, 30322, U.S.A.
authors.forename: M R
authors.initials: MR
authors.lastname: Sargen
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, U.S.A.
authors.forename: S L
authors.initials: SL
authors.lastname: Merrill
authors.affiliation: Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, U.S.A.|Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, U.S.A.
authors.forename: E Y
authors.initials: EY
authors.lastname: Chu
authors.affiliation: Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, U.S.A. knathans@exchange.upenn.edu.|Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, U.S.A. knathans@exchange.upenn.edu.
authors.forename: K L
authors.initials: KL
authors.lastname: Nathanson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis / Q000235:genetics*; D009442:Neurilemmoma / Q000175:diagnosis; D009456:Neurofibromatosis 1 / Q000175:diagnosis; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D022821:RNA Splice Sites