Abstract IA5: Genetics of clonal progression in pancreatic cancer

The goal of our laboratory is to understand the extent to which genetic features of a neoplasm influence its metastatic progression. Towards this goal we have focused on human pancreatic ductal adenocarcinoma (PDAC) as it represents an ideal tumor type for study of the metastatic process. For example, the precursor lesions that give rise to PDAC have been described in detail (pancreatic intraepithelial neoplasia, or PanIN), exomic sequencing has elucidated the major genetic alterations of this tumor type, and the accumulation of these genetic alterations during PanIN formation underlies the well accepted genetic progression model of pancreatic ductal carcinogenesis. Finally, PDAC is a tumor type that is often diagnosed in the advanced stages of disease and thus most patients have their primary carcinoma in situ for comparison to matched metastatic disease. Such is not the case for many other common human tumor types. We have taken the unique approach of performing rapid autopsies for acquisition of primary and metastatic cancer tissues from a large number of individuals, and have used this resource to make several novel observations related to the timing of acquisition of metastatic traits. First, not all pancreatic cancers are metastatic; of those that do form metastases the range of deposits seen at autopsy ranges from few ( 100 (widely metastatic). Moreover, loss of the SMAD4 tumor suppressor gene that occurs during carcinogenesis is highly correlated with widespread metastatic disease. Second, using a whole exome sequencing approach we have defined the clonal evolution of PDAC. This has shown that the majority of genetic alterations are founder mutations in that they are encompassed with the parental clone of cells that give rise to PDAC, upon which are superimposed additional genetic alterations that accumulate during subclonal evolution. Geographic mapping of subclones based on their unique genetic signatures indicates that metastatic subclones originate within the primary carcinoma; moreover, several years are required for development of metastatic subclones beyond initiation of the infiltrating carcinoma by the parental clone. Thus, even in carcinomas with SMAD4 loss additional events are needed for successful metastasis to occur. Most recently, we have investigated pancreatic cancer progression by utilizing a mathematical framework of metastasis formation together with comprehensive data of PDAC patients obtained at autopsy. This work indicates that primary and metastatic PDAC growth is initially exponential, and that patients with seemingly early stage disease likely harbor metastases at diagnosis. Furthermore, based on the estimating rates of PDAC growth and dissemination, we analyzed the effects of different treatment modalities and found that therapies which efficiently reduce the growth rate of cells earlier in the course of treatment appear to be superior to upfront tumor resection. These lines of investigation not only shed light on this difficult tumor type but also have implications for most other major tumor types for which metastatic progression is common. Citation Format: Christine A. Iacobuzio-Donahue. Genetics of clonal progression in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA5.