title: Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours.
abstract: Malignant peripheral nerve sheath tumours (MPNSTs) are a malignancy occurring with increased frequency in patients with neurofibromatosis type 1 (NF1). In contrast to the well-known spectrum of germline NF1 mutations, the information on somatic mutations in MPNSTs is limited. In this study, we screened NF1, KRAS, and BRAF in 47 MPNSTs from patients with (n = 25) and without (n = 22) NF1. In addition, DNA from peripheral blood and cutaneous neurofibroma biopsies from, respectively, 14/25 and 7/25 of the NF1 patients were analysed. Germline NF1 mutations were detected in ten NF1 patients, including three frameshift, three nonsense, one missense, one splicing alteration, and two large deletions. Somatic NF1 mutations were found in 10/25 (40%) NF1-associated MPNSTs, in 3/7 (43%) neurofibromas, and in 9/22 (41%) sporadic MPNSTs. Large genomic copy number changes accounted for 6/10 and 7/13 somatic mutations in NF1-associated and sporadic MPNSTs, respectively. Two NF1-associated and 13 sporadic MPNSTs did not show any NF1 mutation. A major role of the KRAS and BRAF genes was ruled out. The spectrum of germline NF1 mutations in neurofibromatosis patients with MPNST is different from the spectrum of somatic mutations seen in MPNSTs. However, the somatic events share common characteristics with the NF1-related and the sporadic tumours.
authors.affiliation: IRCCS-CSS, San Giovanni Rotondo and CSS-Mendel Institute, 00198 Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bottillo
authors.forename: Terje
authors.initials: T
authors.lastname: Ahlquist
authors.forename: Helge
authors.initials: H
authors.lastname: Brekke
authors.forename: Stine A
authors.initials: SA
authors.lastname: Danielsen
authors.forename: Eva
authors.initials: E
authors.lastname: van den Berg
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins