title: Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs).
abstract: About 10% of neurofibromatosis type 1 (NF1) patients develop malignant peripheral nerve sheath tumors (MPNSTs) and represent considerable patient morbidity and mortality. Elucidation of the genetic mechanisms by which inherited and acquired NF1 disease gene variants lead to MPNST development is important. A study was undertaken to identify the constitutional and somatic NF1 mutations in 34 MPNSTs from 27 NF1 patients. The NF1 germline mutations identified in 22 lymphocytes DNA from these patients included seven novel mutations and a large 1.4-Mb deletion. The NF1 germline mutation spectrum was similar to that previously identified in adult NF1 patients without MPNST. Somatic NF1 mutations were identified in tumor DNA from 31 out of 34 MPNSTs, of which 28 were large genomic deletions. The high prevalence (>90%) of such deletions in MPNST contrast with the =or<20% found in benign neurofibromas and is indicative of the involvement of different mutational mechanisms in these tumors. Coinactivation of the TP53 gene by deletion, or by point mutation along with NF1 gene inactivation, is known to exacerbate disease symptoms in NF1, therefore TP53 gene inactivation was screened. DNA from 20 tumors showed evidence for loss of heterozygosity (LOH) across the TP53 region in 11 samples, with novel TP53 point mutations in four tumors.
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom. Upadhyaya@cardiff.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
authors.forename: G
authors.initials: G
authors.lastname: Spurlock
authors.forename: Bisma
authors.initials: B
authors.lastname: Monem
authors.forename: E
authors.initials: E
authors.lastname: Majounie
authors.forename: K
authors.initials: K
authors.lastname: Mantripragada
authors.forename: Martino
authors.initials: M
authors.lastname: Ruggieri
authors.forename: N
authors.initials: N
authors.lastname: Chuzhanova
authors.forename: D G
authors.initials: DG
authors.lastname: Evans
authors.forename: R
authors.initials: R
authors.lastname: Ferner
authors.forename: N
authors.initials: N
authors.lastname: Thomas
authors.forename: A
authors.initials: A
authors.lastname: Guha
authors.forename: V
authors.initials: V
authors.lastname: Mautner
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000378:metabolism; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000378:metabolism; D009154:Mutation; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism; D010524:Peripheral Nervous System Neoplasms / Q000235:genetics*; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; D025542:Neurofibromin 1; D016159:Tumor Suppressor Protein p53