A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants atDPYDand a putative role forENOSF1rather thanTYMS

Abstract

ObjectiveCapecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS).DesignWe investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial.ResultsWe identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10−6) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10−5). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10−8). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10−6). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5′VNTR 2R/3R and 3′UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression.ConclusionsDPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1.

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

“…A set of studies [26][27][28][29][30] highlighted the pivotal role of DPYD gene polymorphisms in the insurgence of severe toxicity and led to the definition of pharmacogenetic guidelines for the diagnostic use of some DPYD SNPs testing (i.e., DPYDrs3918290, DPYD-rs67376798, and DPYD-rs55886062). 1 These results were further validated in successive studies which assessed the role of these SNPs in prospective clinical trials, 3,8,9 in retrospective patients collections 7,10,11 and in meta-analysis studies. 17,18 Despite the efforts of the scientific community to thrust the introduction of the DPYD pharmacogenetic tests in the everyday clinical practice for FL treatment personalization, clinicians only occasionally decide to rely on these clinical tools.…”

“…3 1 patient was treated with CAPOXIRI regimen and one patient was treated with DOC regimen. 4 Maximum grade of toxicity developed within the first three drug administrations.…”

“…Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug-related genetic tests and …”

“…1 Despite the acknowledged efficacy of these drugs in the treatment of different solid tumors, 2 the FL treatment remains challenging as a result of a considerable inter-patient variability in terms of efficacy and toxicity. 3,4 The pharmacogenetic research, aimed at defining predictive markers of FL response, mainly focused on the dihydropyrimidine dehydrogenase (DPD), which is the first and rate-limiting enzyme of FL catabolic pathway. Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities.…”

“…Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug-related genetic tests and their integration in the clinical routine. In particular, the Clinical Pharmacogenetics Implementation Consortium (CPIC) 12,13 and the Dutch Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (DPWG) 14 have published drug-specific guidelines based on the patient genotype.…”