Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis.

Hamzic, Seid; Kummer, Dominic; Froehlich, Tanja K.; Joerger, Markus; Aebi, Stefan; Palles, Claire; Thomlinson, Ian; Meulendijks, Didier; Schellens, Jan H M; García-González, Xandra; López-Fernández, Luis A; Amstutz, Ursula; Largiadèr, Carlo R. (2020). Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis. Pharmacological research, 152, p. 104594. Elsevier 10.1016/j.phrs.2019.104594

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To assess the proposed associations of the c.742-227G>A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidine-treated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p < 0.0001, per allele). We observed independent effects for ENOSF1 c.742-227G>A and the TYMS 28bp-repeat: each toxicity-associated allele increased the risk for severe HFS (OR = 1.32 per allele, p < 0.0001). Patients homozygous for both variants were at the 3-fold higher risk for severe HFS compared to wild-type patients. Our results confirm an essential role for ENOSF1 c.742-227G and TYMS 2R-alleles in the development of fluoropyrimidine-related HFS. This suggests an important function of these genes in the development of severe HFS. Furthermore, these variants might help stratify patients in studies investigating measures of HFS prevention.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Hamzic, Seid, Fröhlich, Tanja, Amstutz, Ursula, Largiadèr, Carlo Rodolfo


600 Technology > 610 Medicine & health








Karin Balmer

Date Deposited:

30 Jul 2020 15:33

Last Modified:

05 Dec 2022 15:39

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Capecitabine ENOSF1 Fluorouracil Hand-foot-syndrome TYMS





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