Data from <i>BRCA1</i> Loss Preexisting in Small Subpopulations of Prostate Cancer Is Associated with Advanced Disease and Metastatic Spread to Lymph Nodes and Peripheral Blood

Abstract

<div>Abstract<p><b>Purpose:</b> A preliminary study performed on a small cohort of multifocal prostate cancer (PCa) detected <i>BRCA1</i> allelic imbalances among circulating tumor cells (CTC). The present analysis was aimed to elucidate the biological and clinical roles of <i>BRCA1</i> losses in metastatic spread and tumor progression in PCa patients.</p><p><b>Experimental Design:</b> To map molecular progression in PCa outgrowth, we used fluorescence <i>in situ</i> hybridization analysis of primary tumors and lymph node sections, and CTCs from peripheral blood.</p><p><b>Results:</b> We found that 14% of 133 tested patients carried monoallelic <i>BRCA1</i> loss in at least one tumor focus. Extended molecular analysis of chr17q revealed that this aberration was often a part of larger cytogenetic rearrangement involving chr17q21 accompanied by allelic imbalance of the tumor suppressor gene <i>PTEN</i> and lack of <i>BRCA1</i> promoter methylation. The <i>BRCA1</i> losses correlated with advanced T stage (<i>P</i> < 0.05), invasion to pelvic lymph nodes (<i>P</i> < 0.05), as well as biochemical recurrence (<i>P</i> < 0.01). Their prevalence was twice as high within 62 lymph node metastases (LNM) as in primary tumors (27%, <i>P</i> < 0.01). The analysis of 11 matched primary PCa-LNM pairs confirmed the suspected transmission of genetic abnormalities between these two sites. In four of seven patients with metastatic disease, <i>BRCA1</i> losses appeared in a minute fraction of cytokeratin- and vimentin-positive CTCs.</p><p><b>Conclusions:</b> Small subpopulations of PCa cells bearing <i>BRCA1</i> losses might be one confounding factor initiating tumor dissemination and might provide an early indicator of shortened disease-free survival. Clin Cancer Res; 16(13); 3340–8. ©2010 AACR.</p></div>