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Biallelic and complicated inactivation of Pten in radiation-induced mouse thymic lymphomas


ABSTRACT: Inactivation of Pten occurs by multiple mechanisms including epigenetic silencing, point mutations, insertion, and deletion, which are tissue dependent. Although frequent loss of heterozygosity around Pten locus and plausible involvement of epigenetic silencing have been reported in radiation-induced thymic lymphomas, the frequency of Pten inactivation and the spectrum of causal aberrations have not yet been extensively characterized. Here, we assessed the principal mode of inactivation by comprehensively analyzing expression and alterations of Pten gene in 23 radiation-induced thymic lymphomas developed in B6C3F1 mice. We found no evidence for methylation-associated silencing of Pten gene. Instead, we found complex structural abnormalities in 8 lymphomas (35%) that included missense and nonsense mutations, 1- and 3-bp insertions, and focal deletions. Sequencing of deletion breakpoints suggested that illegitimate V(D)J recombination and microhomology-mediated rearrangement were responsible for the focal deletions. Seven out of these 8 lymphomas had biallelic alterations, and 4 of them did not express any Pten protein. These aberrations of Pten were well coincided with downstream Akt phosphorylation on Ser473. In conclusion, Pten inactivation, which is frequently biallelic and is caused by a variety of structural abnormalities but not by epigenetic silencing, is involved in radiation-induced lymphomagenesis. Overall design: Three thymic lymphomas were analyzed by array-CGH method.

INSTRUMENT(S): Mouse custom CGH oligo array 15K (020410)

ORGANISM(S): Mus musculus  

SUBMITTER: Takashi Takabatake   

PROVIDER: GSE17751 | GEO | 2010-03-01

SECONDARY ACCESSION(S): PRJNA118355

REPOSITORIES: GEO

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