Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer

Abstract

Objective: Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. Methods: We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. Results: After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. Conclusions: Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC.

DCK expression, a potential predictive biomarker in the adjuvant gemcitabine chemotherapy for biliary tract cancer after surgical resection: results from a phase II study

“…Several genetic and epigenetic alterations, including gene mutations, amplifications, polymorphic status or altered gene/protein expression and activity, have been associated with gemcitabine response and toxicities [ 20 , 25 ]. In our previous retrospective study of patients with advanced BTC who were treated with gemcitabine plus cisplatin, the variant rs1048977 allele in the CDA gene was associated with tumor response in a dominant model [ 14 ]. In the present study, however, none of the tested SNPs was significantly associated with RFS or with hematologic or non-hematologic toxicities.…”

“…However, these were small-scale or retrospective studies. Our group recently reported that a polymorphism in the gene encoding cytidine deaminase (CDA) may predict the efficacy of gemcitabine-based chemotherapy in patients with advanced BTC [ 14 ]. Deoxycytidine kinase (dCK) is a key enzyme that activates gemcitabine by phosphorylation.…”

Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation

“…Data on the relationship between CDA polymorphisms and GCB toxicity are inconsistent (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Severe GCB toxicity in NSCLC patients was reported in cases with heterozygous c.437CT variant and, to a lesser degree, in those with homozygous c.435TT variant (25,26).…”

“…2-35 (11-15). Data regarding toxicity related to CDA polymorphisms are inconsistent (16)(17)(18). Nevertheless, several studies demonstrated that single nucleotide polymorphism (SNP) of CDA c.79 A>C, c.208 G>A and c.435C>T, with resulting decreased serum CDA concentration, may lead to severe toxicity induced by GCB (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

“…96 In vitro, macrophage-induced CDA upregulation in human Panc-1 pancreatic tumor cell line has been shown to confer gemcitabine resistance. 111 Data from ample studies have indicated that CDA polymorphisms alter CDA enzyme activity and the pharmacokinetics of gemcitabine, [135][136][137][138] and three functional polymorphisms of CDA (rs2072671, CDA 79A  C; rs60369023, CDA 208G  A; and rs1048977, CDA 435C  T) could predict the clinical outcomes of gemcitabine-based tumor chemotherapy. 33,135,136 …”