Abstract
SummaryBackgroundScreening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM.MethodsUsing mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation.FindingsOf 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM.InterpretationAdiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM.FundingNorth West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide.[1]
Our results provide a basis for biomarker-driven stratification of individuals with new-onset type diabetes mellitus (NOD) into high or low risk for PDAC, based on whether diabetes is type 3c DM (T3cDM) or type 2 diabetes mellitus (T2DM)
Functional analysis of differentially expressed proteins identified in discovery, with results filtered by disease categories and functions, revealed an enrichment in proteins associated with glucose metabolism disorder (p=1.19£10-13), metabolism of protein (p=1.11£10-12), and diabetes mellitus (p=7.59£10-12)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide.[1] The disease is most often diagnosed at an advanced stage, contributing to the low overall five-year survival of 5-10%. Screening could facilitate earlier detection.[2] PDAC is uncommon, occurring at an annual incidence of 5-17 per 100,000 population worldwide. Only screening tests with specificities close to 100% would avoid large numbers of false positives. CA19-9, the only biomarker routinely used for the clinical management of PDAC, suffers from poor specificity and cannot be used as a stand-alone diagnostic for screening
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