Multi-Omic Biomarkers as Potential Tools for the Characterisation of Pancreatic Cystic Lesions and Cancer: Innovative Patient Data Integration

Abstract

Pancreatic cancer (PC) is regarded as one of the most lethal malignant diseases in the world, with GLOBOCAN 2020 estimates indicating that PC was responsible for almost half a million deaths worldwide in 2020. Pancreatic cystic lesions (PCLs) are fluid-filled structures found within or on the surface of the pancreas, which can either be pre-malignant or have no malignant potential. While some PCLs are found in symptomatic patients, nowadays many PCLs are found incidentally in patients undergoing cross-sectional imaging for other reasons-so called 'incidentalomas'. Current methods of characterising PCLs are imperfect and vary hugely between institutions and countries. As such, there is a profound need for improved diagnostic algorithms. This could facilitate more accurate risk stratification of those PCLs that have malignant potential and reduce unnecessary surveillance. As PC continues to have such a poor prognosis, earlier recognition and risk stratification of PCLs may lead to better treatment protocols. This review will focus on the importance of biomarkers in the context of PCLs and PCand outline how current 'omics'-related work could contribute to the identification of a novel integrated biomarker profile for the risk stratification of patients with PCLs and PC.

Keywords: biomarker; multi-omics; omics; pancreatic cancer; pancreatic cystic lesion; risk.

Figure 1

Molecular subgroups of pancreatic cystic lesions. Intraductal papillary mucinous neoplasms (IPMNs) and their distinct subclassifications are highlighted. IPMNs are the most common subgroup and are responsible for 38% of PCLs, while mucinous cystic neoplasms, serous cystic neoplasms and cystic neuroendocrine neoplasm represent 23%, 16% and 7% of PCLs, respectively [29]. Branch-duct IPMNs are most common (46%), followed by combined-type IPMNs (40%) and main-duct IPMNs (14%) [30].

Figure 2

The multi-omic nature of KRAS mutations in pancreatic cancer. (A) Environmental factors cause biochemical alterations to the DNA such as hypermethylation. This can result in the silencing of repair genes and subsequently failure in DNA repair pathways; (B) Point mutations in a KRAS codon go unchecked as a result of DNA repair failure causing permanent activation of KRAS gene; (C) Mutant KRAS gene is transcribed into mRNA and subsequently results in an upregulation of miR-34a and miR-31 and a downregulation in miR143 and miR-145; (D) mutant KRAS mRNA cannot be bound by regulatory miR let-7 and leaves the cell nucleus to be translated; (E) Mutant KRAS causes an increase in K-Ras protein expression, which causes activation of PI3K, MAPK and RAL-GEF pathways; (F) GTP bound KRAS interacts with various effector proteins and influences the localisation and activities of these effectors; (G) K-Ras proteins convert GTP to GDP which causes gene deactivations and metabolic alterations such as an increase in GLUT1 expression and subsequently an increase in glucose uptake via glycolysis; (H) Changes to cellular protein expression, gene activation and metabolic processes results in increased cell growth and proliferation, driving transformation.