Abstract
Abstract Perp, a tetraspan plasma membrane protein, is activated by p53 during apoptosis and is also regulated by p63 where it functions as an essential component of the desmosome and contributes to epithelial integrity. A single nucleotide polymorphism (SNP) in Perp was identified by its effect on apoptotic efficiency in irradiated lymphoblastoid cell lines. Therefore, this SNP may have functional significance in clinical outcomes of cancer. In this study, this SNP in PERP was evaluated as a prognostic marker and in its relationship to other known prognostic factors. Genotyping was performed on DNA isolated from peripheral blood of 1020 patients with breast cancer and genotypes were linked with annotated clinical information. Analysis of recurrence free survival was performed on a subset limited to 790 Caucasians. Among Caucasian cases, homozygous SNP genotypes were nearly equally distributed (AA: 25% and GG: 26%). Using a COX proportional hazards survival analysis, the AA genotype was found to be an independent predictor of worse recurrence-free survival (RFS, hazard ratio [HR]: 1.95, 95% CI: 1.38-2.76, p=0.0001). RFS was similar between AG and GG carriers and was more favorable as compared to AA carriers. For patients receiving breast-conserving surgery followed by radiation, patients diagnosed at or above 51 years of age or patients with stage III disease, the deleterious effect of AA genotype on RFS was more significant. In addition, the AA genotype associated with decreased RFS in subgroups of Caucasian cases regardless of stratification by hormone receptor status, HER2 status, and whether they received chemotherapy or hormonal therapy. Adjusting for effects due to stage and chemotherapy, this association remained significant in estrogen receptor positive and progesterone receptor negative cases. We also analyzed the NCI-60 cell line panel for an association between this polymorphism and response to 132 standard chemotherapeutic drugs. A significant association was observed with respect to genotype and response to anti-mitotic agents. Collectively, cell lines with the AA genotype were more sensitive to anti-mitotic agents than the GG genotype. Clinical data suggest that the AA genotype of Perp has a functional phenotype leading to increased risk of recurrence. Further studies are needed to determine the mechanism behind this association, but ultimately this SNP may be useful as a prognostic marker in breast cancer and could be used as a tool to optimize treatment strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 681. doi:1538-7445.AM2012-681
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