title: Complicated biallelic inactivation of Pten in radiation-induced mouse thymic lymphomas.
abstract: Inactivation of the phosphatase and tensin homolog gene (Pten) occurs via multiple tissue-dependent mechanisms including epigenetic silencing, point mutations, insertions, and deletions. Although frequent loss of heterozygosity around the Pten locus and plausible involvement of epigenetic silencing have been reported in radiation-induced thymic lymphomas, the proportion of lymphomas with inactivated Pten and the spectrum of causal aberrations have not been extensively characterized. Here, we assessed the mode of Pten inactivation by comprehensive analysis of the expression and alteration of Pten in 23 radiation-induced thymic lymphomas developed in B6C3F1 mice. We found no evidence for methylation-associated silencing of Pten; rather, complex structural abnormalities comprised of missense and nonsense mutations, 1- and 3-bp insertions, and focal deletions were identified in 8 of 23 lymphomas (35%). Sequencing of deletion breakpoints suggested that aberrant V(D)J recombination and microhomology-mediated rearrangement were responsible for the focal deletions. Seven of the 8 lymphomas had biallelic alterations, and 4 of them did not express Pten protein. These Pten aberrations coincided with downstream Akt phosphorylation. In conclusion, we demonstrate that Pten inactivation is frequently biallelic and is caused by a variety of structural abnormalities (rather than by epigenetic silencing) and is involved in radiation-induced lymphomagenesis.
authors.affiliation: Department of Biology, Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Takabatake
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kakinuma
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Amasaki
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nishimura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Imaoka
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Yi
authors.initials: Y
authors.lastname: Shang
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi-Imamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nogawa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D000483:Alleles; D000818:Animals; D055028:Comparative Genomic Hybridization; D015870:Gene Expression; D019656:Loss of Heterozygosity; D051379:Mice; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015854:Up-Regulation
chemical_list: D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase