Integrated Genomic-Transcriptomic Characterization to Identify Molecular Mechanisms of Disparities in PDAC Outcomes

Abstract Despite advances in diagnostic and therapeutic modalities, the 5-year survival of patients with pancreatic adenocarcinoma (PDAC) remains woefully low. Unfortunately, African Americans (AA) bear a disproportionate brunt of this disease and both the incidence and mortality of PDAC are higher amongst them. Better

understanding of the causes of these disparities will help develop novel strategies to address them. Pancreatic cancer is a mutation-driven cancer. Alterations in tumor driver genes like KRAS, TP53, SMAD4 and CDKN2A alter multiple transcriptional pathways in the native pancreatic cells and their microenvironment,

resulting in tumor growth, progression and metastases. Presence or absence of many of these mutations can modulate the aggressiveness of cancer and the clinical course of patients with PDAC. Studies in other cancers including colon, breast and prostate cancer, have demonstrated that differing genomic and

transcriptional landscape amongst Caucasians (CA) and AA can explain some of the racial health disparities with respect the incidence and the outcomes of these cancers. However, such data in the context of PDAC is lacking. Given that a) genomic-transcriptomic signatures shape PDAC progression and outcomes; b) AAs and CAs have difference in pancreatic cancer incidence and outcomes irrespective of tumor

stage; and c) race is associated with differential mutational and transcriptional signatures in multiple other cancers, we have put forth the following hypothesis to explain the racial health disparities in context of PDAC: Hypothesis: Differences in the genomic and transcriptomic signatures contributes to the disparities in

pancreatic cancer incidence and outcomes between African Americans and Caucasians. Our hypothesis will be tested through the two specific aims: Aim 1 will be focused on interrogating the mutational landscape of PDAC using deep whole exome sequencing (WES) on resected tumor specimens of histologically proven

PDAC cases from AA PDAC patients. In addition to testing specific hypotheses about KRAS, we will screen for potential pathogenic variants (PPVs) which could be contributing significantly to the outcome disparities between CA and AA PDAC patients. In Aim 2 Bulk RNA sequencing (RNA-seq) will be performed on the

cohort of 100 PDAC specimens from AA patients (from aim 1) to identify clinically relevant transcriptional pathways in AA PDAC tumors in two ways. First, the AA and CA cases will be compared according to our published PurIST algorithm to understand the incidence of classical/basal tumor subtypes, which predict

response to frontline therapy. Additionally, we will perform De-novo transcriptomic subtyping and pathway analysis to understand whether AA PDAC tumors harbor distinct transcriptional signatures compared to those identified previously in CA cases. Successful execution of the current studies will provide, for the first time,

detailed analysis of genetic and transcriptional landscape of PDAC in AAs when compared to CA. These data will help us better understand the potential reasons of racial health disparities and will help us develop novel strategies to address these and thus achieve racial health equality.