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Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs)

Upadhyaya, Meena, Kluwe, Lan, Spurlock, Gillian, Monem, Bisma Qamar, Majounie, Elisa ORCID:, Mantripragada, Kiran Kumar ORCID:, Ruggieri, Martino, Chuzhanova, Nadia, Evans, D. G., Ferner, R., Thomas, Nicholas Stuart Tudor, Guha, A. and Mautner, Victor 2008. Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Human Mutation 29 (1) , pp. 74-82. 10.1002/humu.20601

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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 (490%) of such deletions in MPNST contrast with the Z20% 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: neurofibromatosis type 1; malignant peripheral nerve sheath tumor; NF1; germline mutations; somatic mutations; TP53
Publisher: Wiley Blackwell
ISSN: 1059-7794
Last Modified: 19 Oct 2022 09:55

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