Gene Variants That Affect Levels of Circulating Tumor Markers Increase Identification of Patients With Pancreatic Cancer

Abstract

Background & aims: Levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA-125) in blood are used as markers to determine the response of patients with cancer to therapy, but are not used to identify patients with pancreatic cancer.

Methods: We obtained blood samples from 504 patients undergoing pancreatic surveillance from 2002 through 2018 who did not develop pancreatic cancer and measured levels of the tumor markers CA19-9, CEA, CA-125, and thrombospondin-2. Single-nucleotide polymorphisms (SNPs) in FUT3, FUT2, ABO, and GAL3ST2 that have been associated with levels of tumor markers were used to establish SNP-defined ranges for each tumor marker. We also tested the association between additional SNPs (in FUT6, MUC16, B3GNT3, FAM3B, and THBS2) with levels of tumor markers. To calculate the diagnostic specificity of each SNP-defined range, we assigned the patients under surveillance into training and validation sets. After determining the SNP-defined ranges, we determined the sensitivity of SNP-adjusted tests for the tumor markers, measuring levels in blood samples from 245 patients who underwent resection for pancreatic ductal adenocarcinoma (PDAC) from 2010 through 2017.

Results: A level of CA19-9 that identified patients with PDAC with 99% specificity had 52.7% sensitivity. When we set the cut-off levels of CA19-9 based on each SNP, the test for CA19-9 identified patients with PDAC with 60.8% sensitivity and 98.8% specificity. Among patients with FUT3 alleles that encode a functional protein, levels of CA19-9 greater than the SNP-determined cut-off values identified 66.4% of patients with PDAC, with 99.3% specificity. In the validation set, levels of CEA varied among patients with vs without SNP in FUT2, by blood group, and among smokers vs nonsmokers; levels of CA-125 varied among patients with vs without the SNP in GAL3ST2. The use of the SNPs to define the ranges of CEA and CA-125 did not significantly increase the diagnostic accuracy of the assays for these proteins. Combining data on levels of CA19-9 and CEA, CA19-9 and CA-125, or CA19-9 and thrombospondin-2 increased the sensitivity of detection of PDAC, but slightly reduced specificity.

Conclusions: Including information on SNPs associated with levels of CA19-9, CEA, and CA-125 can improve the diagnostic accuracy of assays for these tumor markers in the identification of patients with PDAC. Clinicaltrials.gov no: NCT02000089.

Keywords: Diagnosis; Early Detection; Genotype; Screening.

Figure 1.

Schematic outline of SNP subgroups for CA19-9, CEA and CA125.

Figure 2.

SNP-stratified tumor marker levels in (A) discovery set, (B) validation set controls. For CA19-9, discovery set controls; FUT3+/+ versus FUT3+/−, p=0.0038; all other comparisons, p<0.0001; for validation set controls all comparisons were p<0.001. CEA levels in discovery set controls were lower in FUT2+/non-blood group B (FUT2+/non-B) than all other groups; in the validation set, levels in the FUT2+/non-B group were lower than FUT2−/non-B and FUT2+/B groups controls (p=0.04 for both). For CA125, GAL3ST2 rs12469459-AA subjects had higher levels than rs12469459-TT and rs12469459-AT carriers (P=0.0007 and <0.0001, respectively, discovery set; both p=0.001, validation set). Rs12469459-TT carriers had lower levels than rs12469459-AT carriers (p=0.062 validation set, p=0.028 combined set). FUT2+ subjects include FUT2+/+ and FUT2+/−.

Figure 3.

SNP-stratified tumor marker levels in patients with localized pancreatic ductal adenocarcinoma: All PDAC cases (top panel), Stage I cases only (bottom panel). CA19-9 levels differed within SNP subgroups (FUT2−/− versus other groups and FUT3−/− versus other groups, p<0.00001, Mann-Whitney).