Complicated biallelic inactivation of Pten in radiation-induced mouse thymic lymphomas.
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.
Yamaguchi
Yu
Y
Department of Biology, Graduate School of Science, Chiba University, Yayoicho, Inage-ku, Chiba 263-8522, Japan.
Takabatake
Takashi
T
Kakinuma
Shizuko
S
Amasaki
Yoshiko
Y
Nishimura
Mayumi
M
Imaoka
Tatsuhiko
T
Yamauchi
Kazumi
K
Shang
Yi
Y
Miyoshi-Imamura
Tomoko
T
Nogawa
Hiroyuki
H
Kobayashi
Yoshiro
Y
Shimada
Yoshiya
Y
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
D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase