Z Gastroenterol 2015; 53 - A2_5
DOI: 10.1055/s-0034-1397099

A common FUT2 variant correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary sclerosing cholangitis

A Wannhoff 1, T Folseraas 2, M Brune 3, C Rupp 1, K Friedrich 1, J Knierim 1, KH Weiss 1, C Flechtenmacher 4, P Schirmacher 4, W Stremmel 1, JR Hov 2, DN Gotthardt 1
  • 1University Hospital Heidelberg, Department of Internal Medicine IV, Heidelberg, Germany
  • 2Oslo University Hospital, Rikshospitalet, Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo, Norway
  • 3University Hospital Heidelberg, Department of Internal Medicine I and Clinical Chemistry, Heidelberg, Germany
  • 4University Hospital Heidelberg, Institue of Pathology, Heidelberg, Germany

Primary sclerosing cholangitis (PSC) can be complicated by the development of biliary malignancy as cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCA). Besides the most commonly used serum screening parameter, namely CA19 – 9, screening with serum levels of carcinoembryonic antigen (CEA) is less examined. We thus conducted a study to investigate carcinoembryonic antigen (CEA) as a screening parameter for biliary malignancy in PSC patients. Based upon findings of a recent genome-wide association study that described an association between the genes of fucosyltransferases (FUT) and CEA, we thought to analyze how serum CEA levels were affected by common genetic variants of FUT2 and FUT3.

In a retrospective cohort analysis we evaluated CEA levels in 226 PSC patients treated at the University Hospital Heidelberg. Among them were 19 with biliary malignancy. We investigated how FUT2 and FUT3 SNPs affected CEA levels. A receiver operating characteristic (ROC) analysis was performed. Optimal cut-off values for CEA were determined based on Youden's index. A validation cohortof 240 patients, including 28 with biliary malignancy, treated at the University Hospital Oslo was included.

Median CEA concentration was lower in cancer-free patients (1.4 ng/mL, IQR: 0.9 – 2.1) than in cancer patients (2.0 ng/mL, IQR: 1.4 – 3.8, P= 0.014). ROC analysis revealed an area under the curve (AUC) of 0.671 and the optimal cut-off was 3.2 ng/mL. The FUT2 variant rs601338 (G428A) correlated with CEA levels (P < 0.001 according to Kruskal-Wallis test): Median CEA values according to genotype were 1.1 ng/mL (IQR: 0.7 – 1.6) for wild-type, 1.4 ng/mL (IQR: 0.9 – 1.9) for heterozygous mutated, and 2.1 ng/mL (IQR: 1.4 – 2.9) for homozygous mutated. This effect was as well found and even more prominent in a subgroup of patients genetically incapable of expressing CA19 – 9. Overall, the AUC improved if ROC analysis was performed separately for FUT2 wild-type (AUC: 0.731) and homozygous mutant (AUC: 0.816) G428A. In contrast, the use of CEA resulted in a diminished ability to discriminate between cancer and no cancer in patients with a heterozygous mutation (AUC: 0.610). These results are reflected in different optimal cut-off values according to FUT2 genotype. The cut-off was 2.2 ng/mL for the wild-type group, 1.5 ng/mL for the heterozygous mutant group and 26.2 ng/mL ind the homozygous mutant group. The influence of FUT2 on CEA was confirmed in the validation cohort.

In conclusion, CEA is suitable for biliary-malignancy screening in PSC patients, especially in patients who do not express CA19 – 9. This is the first study to show that the combined use of CEA measurement and FUT genotyping is clinically beneficial and that it might enhance the early detection of biliary malignancy in clinical practice. This approach could also be effective when screening for other common gastrointestinal malignancies.

Corresponding author: Wannhoff, Andreas

E-Mail: andreas_wannhoff@med.uni-heidelberg.de