Abstract 4831: Monoclonal origin of multifocal cancer and the step-wise genetic events of prostate carcinogenesis

Prostate cancer is commonly detected as multiple foci in a single prostate gland and it is of etiological and clinical importance to identify the origin of these multifocal cancer lesions. Due to the limited number of markers analyzed, previous studies to address this issue are inconclusive. A high-resolution genome-wide study should address this issue better. Therefore, we have performed a genome-wide analysis using Affymetrix Array 6.0 of individually laser-capture microdissected foci to compare the genetic similarities and/or differences of these foci within the same prostate gland. Fluorescence in situ hybridization was used to confirm SNP array results. A total of 43 cancer and high-grade prostatic intraepithelial neoplasia (PIN) foci from 16 prostate cancer cases were analyzed for genomic copy number changes. Copy number changes from same-case foci were compared to determine the genetic relationship between the foci. In many cases, we found extensive genetic differences between different foci isolated from the same case. However, omniclonal copy number gains and losses were detected in 11/11 informative case-matched multifocal tumor cases and 8/8 informative case-matched PIN and tumor cases, suggesting that multiple cancer foci arise from a common prostate cancer precursor clone. In addition, a higher degree of similarity was observed between PIN and adjacent cancer foci, as compared to distant lesions. The strong genetic similarities between PIN and prostate cancer foci from the same region suggest clonal expansion of separate PIN lesions to invasive cancer. Based on the monoclonal model, we examined the step-wise accumulation of these genomic copy number changes. Loss of 10q23.2-10q23.31 and 16q were commonly shared in same-case tumor foci and, in many cases, also matched PIN foci, suggesting that they are early events in prostate carcinogenesis. Other common genomic changes, such as loss of 6q, 8p and 21q22.2-21q22.3, were found less frequently in all same-case foci and rarely in PIN lesions, suggesting these genetic events occur at a relatively later stage. In conclusion, using a high-density SNP array, we reveal a monoclonal origin for the majority of multifocal prostate cancer samples analyzed. From these SNP array data, we have also begun to elucidate the step-wise genetic events in prostate carcinogenesis, including early events such as loss of 10q23.2-10q23.31 and 16q Taken together, these findings should significantly enhance our understanding of prostate carcinogenesis and potentially affect the clinical management of this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4831. doi:10.1158/1538-7445.AM2011-4831