Identification of biomarkers and potential therapeutic targets for pancreatic cancer by proteomic analysis in two prospective cohorts

Abstract

Pancreatic cancer (PC) is the deadliest malignancy due to late diagnosis. Aberrant alterations in the blood proteome might serve as biomarkers to facilitate early detection of PC. We designed a nested case-control study of incident PC based on a prospective cohort of 38,295 elderly Chinese participants with ∼5.7 years' follow-up. Forty matched case-control pairs passed the quality controls for the proximity extension assay of 1,463 serum proteins. With a lenient threshold of p < 0.005, we discovered regenerating family member 1A (REG1A), REG1B, tumor necrosis factor (TNF), and phospholipase A2 group IB (PLA2G1B) in association with incident PC, among which the two REG1 proteins were replicated using the UK Biobank Pharma Proteomics Project, with effect sizes increasing steadily as diagnosis time approaches the baseline. Mendelian randomization analysis further supported the potential causal effects of REG1 proteins on PC. Taken together, circulating REG1A and REG1B are promising biomarkers and potential therapeutic targets for the early detection and prevention of PC.

Keywords: Mendelian randomization; biomarker; circulating protein; incident pancreatic cancer; prospective study; risk stratification.

Graphical abstract

Figure 1

Flowchart of the study design n, number of incident PC cases. ^∗Stockport center was excluded from our analysis because no glucose measurement was provided by this center.

Figure 2

The estimated effects of REG1A, REG1B, TNF, and PLA2G1B on PC risks OR indicates the odds ratio per 1-SD increase in the protein expression. Log (OR) indicates the natural logarithm of OR with a 95% confidence interval. Analysis of UKB data was restricted to cases diagnosed within 6 years of follow-up. Results of the meta-analysis (Meta_fix and Meta_ran) and the Mendelian randomization (MR) are shown in red and blue text, respectively. Meta_fix, fixed-effect meta-analysis; Meta_ran, random-effect meta-analysis. p values were derived from conditional logistic regression for DFTJ and UKB, from inverse variance weighted method for Meta_fix, Meta_ran, and MR.

Figure 3

Association between plasma proteins and incident PC risks in the UKB-PPP (A) REG1A. (B) REG1B. (C) TNF. (D) PLA2G1B. The mean times between baseline and diagnosis of PC in each group were 1.0, 2.1, 3.2, 4.2, 5.7, and 6.5 years, respectively. Note that the samples in each group were cumulative, with the last group including all cases and matched controls. n_case, number of PC cases. n_control, number of matched controls. p values were derived from conditional logistic regression. OR indicates the odds ratio per 1-SD increase in the protein expression.

Figure 4

Association of REG1 proteins with different types of incident cancer within 6 years of follow-up (A) REG1A. (B) REG1B. OR indicates the odds ratio per 1-SD increase in the protein expression. Log (OR) indicates the natural logarithm of OR with a 95% confidence interval. n_case, number of incident cases; n_control, number of matched controls. p values were derived from conditional logistic regression.