A common genetic variant of fucosyltransferase 2 correlates with serum carcinoembryonic antigen levels and affects cancer screening in patients with primary sclerosing cholangitis

Abstract

Background: Primary sclerosing cholangitis (PSC) patients are at increased risk of biliary tract cancer, and carcinoembryonic antigen (CEA) serum levels might be used for screening. Objective: To examine cancer screening with CEA in PSC patients and analyse how serum CEA levels are affected by genetic variants of fucosyltransferase (FUT) 2 and 3. Methods: In a retrospective cohort analysis we evaluated CEA levels in 226 PSC patients, including 19 with biliary malignancy, and investigated how FUT2 and FUT3 SNPs affected CEA levels. Receiver-operating-characteristic (ROC) analysis was performed and cut-off values were determined based on Youden's index. A control cohort contained 240 patients, including 28 with biliary malignancy. Results: Median CEA concentration was lower in cancer-free patients (1.4 ng/mL) than in cancer patients (2.0 ng/mL, P ¼ 0.014). ROC analysis revealed an area under the curve (AUC) of 0.671, the optimal cut-off was 3.2 ng/mL. The FUT2 variant rs601338 (G428A) correlated with CEA levels, and the effect was most prominent in a subgroup of patients genetically incapable of expressing CA19-9. The AUC improved if ROC analysis was performed separately for wild-type (AUC: 0.731) and homozygous mutant (AUC: 0.816) G428A. The influence of FUT2 on CEA was confirmed in the control cohort. Conclusions: CEA is interesting 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.

Inflammation But Not Biliary Obstruction Is Associated With Carbohydrate Antigen 19-9 Levels in Patients With Primary Sclerosing Cholangitis

“…11 It was subsequently identified as a risk factor for dominant stenosis (DS) and cholangitis 12 and further studies revealed that FUT2 in combination with FUT3 significantly affects cancer screening in PSC patients. 13,14 Based upon these recent findings that the CA19-9 level in PSC patients with and without biliary malignancy depends on the FUT2 and FUT3 genotype, we hypothesized that these genotypes will also influence CA19-9 levels in PSC patients with cholestasis and SBC. We therefore designed this trial to investigate the influence of cholestasis, SBC and the FUT2/3-genotype on maximum CA19-9 levels in PSC patients.…”

Longitudinal analysis of CA19‐9 reveals individualised normal range and early changes before development of biliary tract cancer in patients with primary sclerosing cholangitis

“…Approximately 10% of patients exhibit single nucleotide polymorphisms within the fucosyltransferase ( FUT ) 3 gene that cause a loss of CA19‐9 synthesis . However, these patients might benefit from screening with carcinoembryonic antigen, which also is not influenced by bacterial cholangitis . Whereas the use of CA19‐9 biosynthesis groups, based on single nucleotide polymorphisms of FUT2 and FUT3, leads to diagnostic improvement, in our experience, CA19‐9 values show high interpersonal variability.…”

“…The study was previously approved by the ethics committee of the University Hospital Heidelberg. The database, which had already been used as a basis for previously published studies, contained all available CA19‐9 and carcinoembryonic antigen values for each included patient until diagnosis of BTC, liver transplantation (LT), death, or until 31 December 2014, whichever came first. CA19‐9 and carcinoembryonic antigen values were derived by chart review.…”

“…Basic demographic and health characteristics for each patient, including information on malignancies, were also derived from the database. Further, genotyping results for FUT2 and FUT3 , which have been shown to influence individual CA19‐9 serum levels, were available for the majority of the patients as well; the genotyping methods have been previously described . The diagnosis of BTC was made by histological examination (including examination of the explanted liver in patients who underwent LT) or by the combination of findings of a mass on imaging and suspicious cytology.…”

An update on cancer risk and surveillance in primary sclerosing cholangitis

“…Carcinoembryonic antigen (CEA) is a glycoprotein involved in cellular adhesion, and a tumor marker that is frequently elevated in gastrointestinal malignancies. A retrospective cohort analysis demonstrated fucosyltransferase 2 and 3 genotyping can also enhance sensitivity of CEA measurements, especially in those patients whom do not express CA 19‐9 …”