title: An imprinted locus epistatically influences Nstr1 and Nstr2 to control resistance to nerve sheath tumors in a neurofibromatosis type 1 mouse model.
abstract: Cancer is a complex disease in which cells acquire many genetic and epigenetic alterations. We have examined how three types of alterations, mutations in tumor suppressor genes, changes in an imprinted locus, and polymorphic loci, interact to affect tumor susceptibility in a mouse model of neurofibromatosis type 1 (NF1). Mutations in tumor suppressor genes such as TP53 and in oncogenes such as KRAS have major effects on tumorigenesis due to the central roles of these genes in cell proliferation and cell survival. Imprinted genes expressed from only one parental chromosome affect tumorigenesis if their monoallelic expression is lost or duplicated. Because imprinted loci are within regions deleted or amplified in cancer, the parental origin of genomic rearrangements could affect tumorigenesis. Gene polymorphisms can vary tumor incidence by affecting rate-limiting steps in tumorigenesis within tumor cells or surrounding stroma. In our mouse model of NF1, the incidence of tumors mutant for the tumor suppressor genes Nf1 and Trp53 is strongly modified by a linked imprinted locus acting epistatically on two unlinked polymorphic loci, Nstr1 and Nstr2. This interaction of an imprinted locus and polymorphic susceptibility loci has profound implications for human mapping studies where the parental contribution of alleles is often unknown.
authors.affiliation: Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA. kreilly@ncifcrf.gov
authors.forename: Karlyne M
authors.initials: KM
authors.lastname: Reilly
authors.forename: Karl W
authors.initials: KW
authors.lastname: Broman
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Shirley
authors.initials: S
authors.lastname: Tsang
authors.forename: Dagan A
authors.initials: DA
authors.lastname: Loisel
authors.forename: Emily S
authors.initials: ES
authors.lastname: Christy
authors.forename: Zhonghe
authors.initials: Z
authors.lastname: Sun
authors.forename: John
authors.initials: J
authors.lastname: Diehl
authors.forename: David J
authors.initials: DJ
authors.lastname: Munroe
authors.forename: Robert G
authors.initials: RG
authors.lastname: Tuskan
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D005260:Female; D016514:Genes, Neurofibromatosis 1; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D011110:Polymorphism, Genetic