title: Therapy-induced malignant neoplasms in Nf1 mutant mice.
abstract: Therapy-induced cancers are a severe complication of genotoxic therapies. We used heterozygous Nf1 mutant mice as a sensitized genetic background to investigate tumor induction by radiation (RAD) and cyclophosphamide (CY). Mutagen-exposed Nf1(+/-) mice developed secondary cancers that are common in humans, including myeloid malignancies, sarcomas, and breast cancers. RAD cooperated strongly with heterozygous Nf1 inactivation in tumorigenesis. Most of the solid tumors showed loss of the wild-type Nf1 allele but retained two Trp53 alleles. Comparative genomic hybridization demonstrated distinct patterns of copy number aberrations in sarcomas and breast cancers from Nf1 mutant mice, and tumor cell lines showed deregulated Ras signaling. Nf1(+/-) mice provide a tractable model for investigating the pathogenesis of common mutagen-induced cancers and for testing preventive strategies.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Chao
authors.forename: Urszula
authors.initials: U
authors.lastname: Pyzel
authors.forename: Jane
authors.initials: J
authors.lastname: Fridlyand
authors.forename: Yien-Ming
authors.initials: YM
authors.lastname: Kuo
authors.forename: Lewis
authors.initials: L
authors.lastname: Teel
authors.forename: Jennifer
authors.initials: J
authors.lastname: Haaga
authors.forename: Alexander
authors.initials: A
authors.lastname: Borowsky
authors.forename: Andrew
authors.initials: A
authors.lastname: Horvai
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bonifas
authors.forename: Bing
authors.initials: B
authors.lastname: Huey
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Jacks
authors.forename: Donna G
authors.initials: DG
authors.lastname: Albertson
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity*; D016514:Genes, Neurofibromatosis 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology*; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D011878:Radiotherapy / Q000009:adverse effects*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide