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As part of our SU2C studies we are profiling the genomes of primary localized pancreatic ductal adenocarcinomas (PDAs) obtained from surgical samples collected at the University of Pennsylvania (SU2C-003). A fundamental challenge for the study of PDA genomes in clinical samples is the presence of varied admixtures of reactive stroma, inflammatory cells, and necrosis within the tumor. Furthermore, it is well-established that biopsies frequently contain multiple clonal populations of neoplastic cells that cannot be distinguished on the basis of morphology alone. In order to overcome the limitations of histopatholgy-based methods to study PDA genomes, we are using DNA content-based flow cytometry to identify and purify distinct clonal populations from each surgical sample. These assays are done while collecting up to 6 simultaneous sorting streams thus optimizing the use of each clinical sample. Each sorted diploid, aneuploid, and tetraploid population is interrogated with oligonucleotide CGH arrays. In addition, the epithelial and mesenchymal content of each tumor sample is assessed in flow assays with cytokeratin 19, vimentin, and ZEB1. Our unbiased approach provides clonal analysis of distinct populations in each patient’s tumor regardless of tumor cell content. We have identified a series of novel patient-specific selected aberrations, including homozygous deletions that target regulators of chromatin remodeling (SMYD3, ASXL2), and high-level focal amplicons that include mediators of oncogenic signaling pathways (FNTA, RAB3IP) and cellular metabolism (CTPS). The genes targeted by the somatic aberrations in each patient are overlaid onto a collection of 33 PDA-specific maps, containing 763 genes of interest, developed as part of the Metaminer Oncology initiative. These include signaling pathways of aberrant KRAS, DNA repair, apoptosis, epithelial mesenchymal transition (EMT), inflammation, and other mediators of PDA. We have accumulated clonal genomic data for 15 patients in the first 4 months of this study (December 2011- April 2012) and are currently profiling 3-5 new samples per month. These are providing a unique prospective data set to test hypothesis of the genomic basis of clinical outcomes in patients with localized resectable PDA. This proffered talk is also presented as Poster B19. Citation Format: Michael T. Barrett, Elizabeth Lenkiewicz, Lisa Evers, Tara Holley, Meraj Aziz, Edward Stites, Richard Posner, Amy Kramer, Jeffrey Drebin, Daniel D. Von Hoff. Clonal profiling of prospectively collected primary pancreatic ductal adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr PR7.