Transcriptomes and shRNA suppressors in a TP53 allele-specific model of early-onset colon cancer in African Americans.

Abstract

UNLABELLED:

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.

IMPLICATIONS:

TP53 P72R polymorphism significantly contributes to increased African American cancer disparity.

• Authors: Charles C Weige, Marc R Birtwistle, Himel Mallick, Nengjun Yi, Zuzana Berrong, Emily Cloessner, Keely Duff, Josephine Tidwell, Megan Clendenning, Brent Wilkerson, Christopher Farrell, Fred Bunz, Hao Ji, Michael Shtutman, Kim E Creek, Carolyn E Banister, Phillip J Buckhaults
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 12 Issue 7 Pg. 1029-41 (Jul 2014) ISSN: 1557-3125 [Electronic] United States
• PMID: 24743655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• RNA, Messenger
• RNA, Small Interfering

Topics

• Black or African American (genetics)
• Alleles
• Colonic Neoplasms (ethnology, genetics)
• Genes, p53
• Genetic Predisposition to Disease
• Humans
• Polymorphism, Single Nucleotide
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Transcriptome