Proteogenomic analysis demonstrates novel potential targets of pancreatic ductal adenocarcinoma in African patients

Abstract

Pancreatic ductal adenocarcinoma (PDAC) accounts for 2.8% of new cancer cases worldwide and is projected to become the 2nd leading cause of cancer-related deaths by 2030. Patients of African ancestry appear to be at increased risk for PDAC with the worst severity and outcome.This proposed study sought to determine and integrate proteomic and genomic profiles of PDAC patients of African ancestry to identify potential markers and better understand molecular mechanisms of the disease, especially in our population cohort. Thirty tissues (15 tumours and 15 corresponding normal tissues) were obtained from consenting South African PDAC patients undergoing Whipple procedure at Chris Hani Baragwanath Hospital in Johannesburg, South Africa (HREC-M150778). Protein and DNA were extracted from tissue samples and SWATH Mass Spectrometry and OncoArray anlaysis performed. Network and functional analysis were conducted using STRINGv11.0 and REACTOMEv70. We also used the Variant effect predictor (VEPv98) tool to predict consequences of the SNPs observed. We found 55 upregulated and 36 downregulated proteins in tumour samples which were mostly involved in key biological processes, including haemostasis, signal transduction, neuronal system and developmental biology. These aberrant processes are known to exacerbate tumour aggressiveness, invasion and metastasis. Furthermore, we observed 219 SNPs covering key gene regions such as those observed to be upregulated by SWATH-MS analysis. They include genes such as PALLD, AVL9, BPGM, SERPINB8 and MYPN. We have shown the dysregulation and simultaneous mutations of several key genes/proteins highlighting their roles as plausible biomarkers and therapeutic targets. Validation studies are required to confirm these results.