Abstract A006: Differential gene expression to delineate racial disparities in the molecular landscape of pancreatic ductal adenocarcinoma
Authors: Prachi Bajpai, Ravi Paluri, Sameer Al Diffalha, Darshan S. Chandrashekar, Farrukh Afaq, Ryan Bash, C. Ryan Miller, Sooryanarayana Varambally, Moh’d Khushman, Upender Manne
Journal: Cancer Research (2024)

Abstract Introduction: In the US, there are racial disparities in PDAC incidence and mortality, higher among blacks than whites. In addition to socioeconomic status, lifestyles, and age, genetics also contributes to these disparities. Thus, we conducted transcriptomic analyses (RNA-seq) of PDAC samples collected from African American (AA) and Caucasian (CA) patients to identify race/ethnicity-specific gene expression profiles and their related pathways to find determinants that contribute to the aggressive phenotypes of PDACs. This study is relevant to the UAB catchment area, since about 30% of patients with PDAC are AAs. Methodology: Histologically confirmed PDACs (n=40) from AA (9 PDAC and 3 matching normal tissues) and CA (31 PDAC and 5 matching normal tissues) were included in this study. FFPE sections of PDACs and their corresponding normal tissues were macro-dissected for RNA isolation. Whole transcriptomic sequencing was performed with a NextSeq 500/550 platform. Trimmed reads were mapped to a human reference genome (hg38) using HISAT, and gene level read count data were obtained using HTSeq. Differential expression analysis was performed using the DESeq2 bioconductor package. ClusterProfiler/DOSE R packages were used for gene ontology and KEGG pathway enrichment analyses. Genes with log 2-fold change of ≥1 and adjusted P-value &amp;lt;0.05 were considered as differentially expressed. Results: Among the top upregulated genes altered in only AA PDACs, compared to their normal tissues, were RNF144B, TESPA1, KLHL17, H2AX, MDGA1, CDK20, PHLDA3, SLC6A16, PARVG, GATD3, NUDT16, RENBP, RTL8C, C1QTNF1, HLA−DRB5, PARP15, PPP1R16B, RASGRP2, and CHST15. Of note, targeting CHST15, by an RNA oligonucleotide, STNM01 in Phase I/IIa trial on unresectable PDAC patients showed improved overall survival. Additionally, inhibition of KLHL17, an upstream activator of Ras/MAPK, could be a candidate target in PDAC. The KEGG pathways altered in AA PDACs, were glycerophospholipid metabolism; bile secretion; retinol metabolism; regulation of lipolysis in adipocytes; and pantothenate and CoA biosynthesis. In CAs, the top upregulated genes in PDACs, compared to their normal tissues, were PPY, UGT1A10, GPR20, SDR16C5, KLK7, MYBPC1, ITLN1, PADI1, CLCA1, UGT1A9, and SERPINB3.The KEGG pathways altered in CA PDACs, were cellular senescence; AGE−RAGE signaling pathway in diabetic complication; PD−L1 and PD−1 checkpoint pathway; and central carbon metabolism. There were 13 genes differentially modulated in AA PDACs as compared to CA PDACs. The 6 down-regulated were USP17L1, C2CD4D, MMP13, DCUN1D5, and 2 genes without annotations (ENSG00000276345 and ENSG00000280966); the 7 up-regulated genes were SEMA4A, LETM2, HMOX1, OTUB2, MEDAG, VEGFD, and HBA1. Immunohistochemical validation of these markers is in progress. Conclusions: Findings of this study showed distinct gene expression profiles and differentially modulated pathways in AA and CA PDAC patients. These results will aid in identifying aggressive phenotypes and new targets for developing race/ethnicity-based therapeutic interventions. Citation Format: Prachi Bajpai, Ravi Paluri, Sameer Al Diffalha, Darshan S. Chandrashekar, Farrukh Afaq, Ryan Bash, C. Ryan Miller, Sooryanarayana Varambally, Moh’d Khushman, Upender Manne. Differential gene expression to delineate racial disparities in the molecular landscape of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A006.