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

Seid Hamzic, Dominic Kummer, Tanja K Froehlich, Markus Joerger, Stefan Aebi, Claire Palles, Ian Thomlinson, Didier Meulendijks, Jan H M Schellens, Xandra García-González, Luis A López-Fernández, Ursula Amstutz & Carlo R Largiadèr

abstract 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.
   
citation Hamzic S, Kummer D, Froehlich T K, Joerger M, Aebi S, Palles C, Thomlinson I, Meulendijks D, Schellens J H M, García-González X, López-Fernández L A, Amstutz U, Largiadèr C R. Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis. Pharmacol Res 2019; 152:104594.
   
type journal paper/review (English)
date of publishing 12-12-2019
journal title Pharmacol Res (152)
ISSN electronic 1096-1186
pages 104594
PubMed 31838077
DOI 10.1016/j.phrs.2019.104594