Defining the heterogeneity landscape of pancreatic cancer copy number alterations.

Abstract

e15776 Background: Pancreatic cancer (PDAC) is projected to become the second leading cause of cancer related mortality by 2030. Bulk whole genome sequencing studies of PDAC have characterized the landscape of clonal mutations and highlighted the prominence of copy number alterations (CNAs) in PDAC genomes. However, little is known with regards to the extent of sub-clonal heterogeneity of somatic CNAs and it is hypothesized that this heterogeneity is a contributing factor to the limited effectiveness of existing therapies. Methods: We retrieved absolute copy number information using bulk sparse whole genome sequencing of multi-region sampled PDAC samples as well as matching primary-metastasis tumor samples from over 100 patients. In addition, we analyzed copy number variations in a subset of these samples (n = 15) at single-cell resolution (~1000 cells in total). Results: We describe a detailed picture of sub-clonal CNAs genetic heterogeneity. Our results illustrate, among other findings, (1) extensive sub-clonal diversity of CNAs giving rise to many genetically unique sub-clonal cancer populations, (2) somatic mosaicism of chromosomal amplicons in single-cancer cells, (3) variation in the dosage of cancer genes, including the KRAS oncogene, in different tumor sub-clones and (4) somatic alterations, such as amplification of 8q11 containing the metastasis promoting gene IKBKB, associated with primary PDAC progression to liver metastasis. Conclusions: Our results offer an in-depth view of the sub-clonal heterogeneity of somatic CNAs in pancreatic cancer and illustrate ways in which such heterogeneity could lead to therapeutic resistance.