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. 2022 Aug;13(4):1711-1721.
doi: 10.21037/jgo-22-310.

Validation of a genotype-based algorithm that identifies individuals with low, intermediate, and high serum CA19-9 levels in cancer-free individuals and in patients with colorectal cancer

Andreas Wannhoff  1 , Simone Werner  2 , Sha Tao  2 , Hermann Brenner  2 , Daniel N Gotthardt  1
Affiliations

Validation of a genotype-based algorithm that identifies individuals with low, intermediate, and high serum CA19-9 levels in cancer-free individuals and in patients with colorectal cancer

Andreas Wannhoff et al. J Gastrointest Oncol. 2022 Aug.

Abstract

Background: Serum levels of Carbohydrate antigen CA19-9 are determined by the genotype of fucosyltransferases 2 and 3. To validate, possibly modify, and improve a grouping algorithm based on these genotypes.

Methods: CA19-9 levels genotypes and of fucosyltransferase 2 and 3 were analyzed in cancer-free and colorectal cancer patients. Patients were assigned to groups with low (group A), intermediate (B), or high (C) CA19-9 biosynthetic activity based on a previously developed grouping algorithm based on genotype of fucosyltransferases 2 and 3.

Results: Three hundred thirty-eight patients were included (n=177 cancer-free). Of cancer-free patients 7.9%, 75.7%, and 16.4% were assigned to groups A, B, and C, respectively. In colorectal cancer patients it 7.5%, 77.0%, and 15.5%, respectively. There were significant differences between median CA19-9 levels in the three groups (P<0.001) in both cohorts. The T59G single-nucleotid polymorphism in fucosyltransferase 3 had a significant influence on CA19-9 levels in cancer-free group B patients, which led to establishment of subgroups B1 and B2. However, no difference in CA19-9 levels between these subgroups was found in colorectal cancer patients. A receiver-operating characteristic showed similar areas under the curve for original group B as well as for subgroups B1 and B2.

Conclusions: The grouping algorithm based on genotype of fucosyltransferases 2 and 3, which defines groups with distinct CA19-9 serum levels, was validated in cancer-free patients and in colorectal cancer patients. No clinically relevant improvement to the grouping algorithm was identified.

Keywords: Fucosyltransferase; cholangiocarcinoma; colorectal cancer; primary sclerosing cholangitis.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-310/coif). AW is co-owner of a patent for a medical analysis system assessing the risk of cancer based upon CA19-9 or CEA and FUT2- and FUT3 genotype. HB reports funding from German Research Council (DFG). DNG is co-owner of a patent for a medical analysis system assessing the risk of cancer based upon CA19-9 or CEA and FUT2- and FUT3 genotype. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Selection of the study population. This figure shows the way, by which patients were selected for the study, including the number of patients and reasons for exclusion. CRC, colorectal cancer.
Figure 2
Figure 2
Grouping algorithm used for assigning the patients to either one of the three groups based on genetically determined CA19-9 biosynthetic activity. Algorithm representing how we used FUT2 and FUT3 genotypes for assigning the patients to either one of the three groups based on expected enzyme activity: A, no FUT3 activity regardless of FUT2 activity; B, all other FUT2/ FUT3 combinations; and C, no FUT2 activity. These groups represented individuals with genotypes determining low (group A), intermediate (group B), and high (group C) CA19-9 biosynthetic activity, respectively. Based upon an algorithm by Wannhoff et al. (6), permission obtained.
Figure 3
Figure 3
Influence of the FUT2 and FUT3 SNPs on serum CA19-9 levels within the three groups in the cancer-free patients. The FUT2 variant G428A was not associated with CA19-9 levels in any of the three groups (A). For the FUT3 variants T202C (B) and C314T (C), there was a trend towards lower CA19-9 levels in heterozygous mutated than the patients with wild-type genotype in the group corresponding to intermediate biosynthetic activity. For the T1067A variant of FUT3, no difference in CA19-9 level was found (D), while in the group corresponding to intermediate biosynthetic activity, those patients with a heterozygous mutation in the T59G FUT3 variant had significantly lower levels of CA19-9 than the patients with wild-type genotype (E).
Figure 4
Figure 4
Values of CA19-9 levels in patients with and without cancer in groups B1 and B2. (A) In controls, the CA19-9 level was significantly higher in group B2 than in group B1 (P=0.005). CA19-9 levels in the colorectal cancer patients were higher in groups B1 and B2 than in the cancer-free patients. However, no difference in CA19-9 level was found among the patients with colorectal cancer in group B1 compared to those of group B2 (P=0.101). (B) No difference in serum CA19-9 level was observed between the patients with primary sclerosing cholangitis of groups B1 and B2 without biliary tract cancer (P=0.487) nor with biliary tract cancer (P=0.549). However, the CA19-9 levels in cancer patients were higher than those of the cancer-free patients in groups B1 and B2. *P<0.05 and #P>0.05 between groups B1 and B2.
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