SULM – Schweizerische Union für Labormedizin | Union Suisse de Médecine de Laboratoire | Swiss Union of Laboratory Medicine

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1Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, INO-F, CH-3010 Bern, Switzerland, 2Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland, 3Division of Medical Oncology, Cantonal Hospital Lucerne, Spitalstrasse, CH-6000 Lucerne 16, Switzerland

Background: Gene variation in enolase superfamily member 1 (ENOSF1 c.742-227G>A) has recently been suggested to account for the previously reported association between two thymidylate synthase variants (TYMS 5’VNTR 2R/3R and 3’UTR 6 bp ins-del), a gene adjacent to ENOSF1, and toxicity in cancer patients treated with capecitabine (Cp), an oral prodrug of 5-fluorouracil (5-FU). This association, however, has so far only been investigated in Cp-treated patients, whereas the impact of this variant on 5-FU toxicity risk is unknown. The aim of this study was thus to assess the association of ENOSF1 and TYMS variation with severe early-onset toxicity in patients receiving Cp-based and 5-FU-based chemotherapies. Methods: The common TYMS polymorphisms 5’VNTR 2R/3R (rs34743033), 3’UTR 6 bp ins-del (rs34489327), the ENOSF1 variant c.742-227G>A (rs2612091), and a rare dihydropyrimidine dehydrogenase mutation (DPYD rs12132152) were genotyped in 144 Cp-treated patients and in 403 patients receiving 5-FU-based chemotherapy. The association of genotyped variants with overall toxicity, hand-foot syndrome (HFS) and diarrhea was assessed. Results: In Cp-treated patients, the associations of c.742-227G>A in ENOSF1 and rs12132152 in DPYD with toxicity were replicated (Padjusted = 0.054; OR = 1.61; 95% CI 0.99-2.63, OR for G allele; and Padjusted = 0.049; OR = 4.63; 95% CI 1.01-21.4). Moreover, carriers of the TYMS 3’UTR 6 bp insertion experienced more Cp-induced HFS (Padjusted = 0.034; OR = 2.63; 95% CI 1.08-6.67) with a stronger association compared to the ENOSF1 variant. Conversely, no associations of the same candidate variants with toxicity were found in 5-FU-treated patients. Conclusions: A haplotype encompassing the neighboring genes TYMS and ENOSF1, and DPYD rs12132152 may be risk factors for toxicity in Cp-based, but not 5-FU-based chemotherapy. Further investigation of the strongly linked polymorphisms in ENOSF1 (c.742-227G>A) and TYMS (3’UTR 6 bp ins-del) is needed to determine the causal variant(s) underlying the observed effect on the individual susceptibility to Cp-related toxicity.


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