Abstract IA008: The origins and function of copy number alterations in pancreas cancer

Abstract

Abstract Pancreas ductal adenocarcinoma is a devastating disease that lacks effective treatment options. Often considered genetically homogenous, it is initiated by activation of oncogenic Kras and often sustains inactivating mutations in the TP53, CDKN2A, and SMAD4 tumor suppressor genes. However, additionally, advanced full blown PDAC often has a large degree of somatic copy number alterations (CNA) whose significance to disease etiology are poorly understood. Interestingly, gene mutations and copy number events may be interconnected, as TP53 mutations are strongly associated with the emergence of tumors harboring large number of CNAs, detectable chromothripsis, extensive intratumoral heterogeneity, and are often polyploid. Using new mouse modeling and genetic engineering approachs, we have begun to explore the emergence and functionality of copy number alterations in human PDAC. The current presentation will focus on the evolution of highly rearranged tumors that arise in Kras mutant pancreatic epithelial cells that sporadically inactivate p53, as well as the cell extrinsic functions of so-called CDKN2A deletions. The work highlights the fundamental importance of copy number events in PDAC. Citation Format: Scott W. Lowe. The origins and function of copy number alterations in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA008.