African Americans are disproportionately affected by early-onset, high-grade
malignancies. A fraction of this
cancer health disparity can be explained by genetic differences between individuals of African or European descent. Here the wild-type
Pro/Pro genotype at the TP53Pro72Arg (P72R) polymorphism (SNP: rs1042522) is more frequent in African Americans with
cancer than in African Americans without
cancer (51% vs. 37%), and is associated with a significant increase in the rates of
cancer diagnosis in African Americans. To test the hypothesis that Tp53 allele-specific gene expression may contribute to African American
cancer disparities, TP53 hemizygous knockout variants were generated and characterized in the RKO colon
carcinoma cell line, which is wild type for TP53 and heterozygous at the TP53Pro72Arg locus. Transcriptome profiling, using RNAseq, in response to the
DNA-damaging agent
etoposide revealed a large number of Tp53-regulated transcripts, but also a subset of transcripts that were TP53Pro72Arg allele specific. In addition, a
shRNA-library suppressor screen for Tp53 allele-specific escape from Tp53-induced arrest was performed. Several novel RNAi suppressors of Tp53 were identified, one of which, PRDM1β (BLIMP-1), was confirmed to be an Arg-specific transcript. Prdm1β silences target genes by recruiting H3K9 trimethyl (H3K9me3) repressive
chromatin marks, and is necessary for stem cell differentiation. These results reveal a novel model for African American
cancer disparity, in which the TP53
codon 72 allele influences lifetime
cancer risk by driving damaged cells to differentiation through an epigenetic mechanism involving gene silencing.
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