Abstract 5070: Role of p73 di-nucleotide polymorphism in prostate cancer and p73 protein isoform balance

Abstract

Abstract The p73 gene is a member of the p53 tumor suppressor family. Compared to p53, the molecular consequences of and risk factors associated with variants of the p73 gene are not well understood. Prostate cancer (PCa) is the most frequently occurring cancer in men, and the second leading cause of cancer mortality among US men. Available molecular markers for PCa risk of incidence or aggressiveness are currently lacking. Though the mechanism of PCa progression is not well understood, several lines of evidence support a role for a di-nucleotide polymorphism (DNP) in the p73 gene as a risk factor for several cancer types. However, results are inconsistent. We investigated a DNP linked pair of transition changes, G4C14-to-A4T14 (rs1801173), located in the 5′-UTR portion of exon 2 of the p73 gene. The goals of this study were to address the potential associations between p73 DNP (rs1801173) and PCa risk and/or progression, and to discern any detectable disruption of p73 protein isoforms in cells harboring the p73 DNP allele. We have analyzed 1,292 PCa patients and 682 healthy control men. Although we detected no association between p73 DNP and PCa risk (OR =1.02, 95%CI=0.86-1.21), a significant inverse relationship between p73 DNP and PCa aggressiveness (OR = 0.55, 95%CI=0.31-0.99) was detected. Several p73 protein isoforms have been identified and can be grouped into two major categories, TAp73 and ΔNp73, which differ in their N-termini and are transcribed from different promoters. The transcriptionally active TAp73 isoforms are transcribed from the P1 promoter and include the full-length N-terminal sequence encompassing exons 1 through 3. However, the ΔNp73 isoforms are transcribed from promoter P2 and do not contain the N-terminal trans-activation (TA) domain. Therefore, the ΔNp73 protein isoform is dominate negative toward TAp73 because ΔNp73 isoforms are able to form tetramers with TAp73, as well as p53, but do not activate transcription of p73- or p53-target genes. The balance between TAp73 and ΔNp73 is disrupted in many cancer types. In this study, Western Blot analyses of eleven cancer cell lines for p73 protein isoforms indicate that the two cell lines with heterozygous genotype for p73 DNP have higher TAp73/ΔNp73 ratios (TAp73/ΔNp73 = 1.39 and 1.4) than the other wild-type cell lines not harboring the p73 DNP allele (TAp73/ΔNp73 = 0.68 to 0.97). Our combined findings are consistent with an association between the p73 DNP allele and lower risk for PCa aggressiveness by increasing the expressed TAp73/ΔNp73 protein isoform ratio. Citation Format: L. Michael Carastro, Hui-Yi Lin, Hyun Y. Park, Donghwa Kim, Selina Radlein, Kaia K. Hampton, Ardeshir Hakam, Babu Zachariah, Julio M. Pow-Sang, Jong Y. Park. Role of p73 di-nucleotide polymorphism in prostate cancer and p73 protein isoform balance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5070. doi:10.1158/1538-7445.AM2014-5070