title: Transcriptomes and shRNA suppressors in a TP53 allele-specific model of early-onset colon cancer in African Americans.
abstract: 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.
  
  
  CONCLUSIONS
  TP53 P72R polymorphism significantly contributes to increased African American cancer disparity.
authors.affiliation: Authors' Affiliations: Departments of Medicine and.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Weige
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York;
authors.forename: Marc R
authors.initials: MR
authors.lastname: Birtwistle
authors.affiliation: Biostatistics, The University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Himel
authors.initials: H
authors.lastname: Mallick
authors.affiliation: Biostatistics, The University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Nengjun
authors.initials: N
authors.lastname: Yi
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia;
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Berrong
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia;
authors.forename: Emily
authors.initials: E
authors.lastname: Cloessner
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia;
authors.forename: Keely
authors.initials: K
authors.lastname: Duff
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia;
authors.forename: Josephine
authors.initials: J
authors.lastname: Tidwell
authors.affiliation: Department of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, Georgia;
authors.forename: Megan
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery University of California, Davis, Sacramento, California;
authors.forename: Brent
authors.initials: B
authors.lastname: Wilkerson
authors.affiliation: Department of Pharmaceutical and Administrative Sciences School of Pharmacy, Presbyterian College, Clinton;
authors.forename: Christopher
authors.initials: C
authors.lastname: Farrell
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
authors.affiliation: Department of Drug Discovery and Biomedical Sciences South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Hao
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Drug Discovery and Biomedical Sciences South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Shtutman
authors.affiliation: Department of Drug Discovery and Biomedical Sciences South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Creek
authors.affiliation: Department of Drug Discovery and Biomedical Sciences South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: Banister
authors.affiliation: Authors' Affiliations: Departments of Medicine and phillip.buckhaults@gmail.com.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Buckhaults
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D003110:Colonic Neoplasms / Q000208:ethnology* / Q000235:genetics*; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics*; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering
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