The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study

Abstract

Background Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined. Methods In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. We planned a case-control study with all cases of DPYD*2A wild type who developed toxicity ≥G3 and with a cohort of patients who did not present severe toxicities. Then, we tested the additional SNPs: c.2846A>T, c.1679T>G, c.2194G>A. Results From 2011 to 2016, we screened 1827 patients for DPD deficiency; of those, 31 subjects (1.7%) showed DPYD*2A SNP. We selected 146 subjects who developed severe toxicities (Cases) and 220 patients who experienced no or mild toxicities (Controls); 53 patients carried one of the additional SNPs: 35 subjects (66%) fell into the Cases and 18 (34%) into the Controls ( p < 0.0001). c.2194G>A was the most frequent SNP (12.5%) and showed a correlation with neutropenia. We confirmed that c.2846A>T and c.1679T>G were related to various toxicities. Conclusions The additional DPYD polymorphisms could enhance the prevention of fluoropyrimidine toxicity. c.2194G>A is the most frequent polymorphism and it was found to be associated with neutropenia.

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

“…Of the potential 112 articles assessed for eligibility, after considering the inclusion and exclusion criteria, 22 studies were included in the analysis [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Table 3 shows such studies subdivided with respect to the analysed DPYD polymorphisms ( DPYD -PGx), the used phenotyping methods and the presence of clinical monitoring.…”

“…Moreover, as shown in Table 3, three studies have performed a combined DPYD-PGx/phenotyping [27,37,41] approach, and eleven carried out the DPYD-PGx together with clinical monitoring. However, among these, only 2/11 genotyped all the four DPYD SNPs recommended in the CPIC and DPWG guidelines [29,39]; the other studies performed at least one of such SNPs, together with other DPYD genetic variants [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”

“…Second, they found a significant association between DPYD*6 and severe neutropenia. Notably, no patients carrying DPYD*2A (1.7%) had started a FP-based treatment [38]. Negarandeh et al screened the presence of DPYD c.2846A>T, DPYD*6 and DPYD*2A in a population of 73 Iranian patients.…”

<p>Pharmacogenomic Assessment of Patients with Colorectal Cancer and Potential Treatments</p>

“…In a multi-center toxicity evaluation conducted among 17 hospitals in the Netherlands, including 1,181 patients, the four most relevant DPYD mutations, DPYD*2A c.1905 G>A, DPYD*13 c.1679 T>G, c.2846 A>T, and c.1236 G>A/HAPB3 were prospectively genotyped prior to receive a treatment containing a fluoropyrimidine drug (capecitabine or fluorouracil alone or associated with other chemotherapeutic drugs or radiation therapy). 34 29 DPYD*6 c.2194G>A was the prevalent SNP (12.5%), significantly correlated with severe neutropenia. In particular, neutropenia was reported in 50% of patients harboring c.2194G>A (23 out of 46) vs 21% of wild-type genotype (67 out of 320) (OR=3.75, CI=1.98-7.10; P<0.0001).…”

“…The three other mutations were associated with more relevant fluoropyrimidine risk of toxicity: 28 DPYD*2A, c.1905+1 G>A (DPYD:IVS14+1 G>A); DPYD*13, c.1679 T>G; c.2846 A>T. The most well-studied DPYD variant clearly associated with severe or even life-threatening toxicity, DPYD*2A, c.1905+1 G>A (DPYD:IVS14+1 G>A), localized at the exon 14 intron boundary, a splice site mutation, a purine transition at the first nucleotide of the intron 14, functionally consisting of a splicing mutation, determines entire exon 14 skipping and translation in a protein nonfunctional effectiveness. 29 Thus, the heterozygous genotype consisting of mutated and wild-type alleles determines 50% reduction of its effectiveness; bi-allelic mutation or homozygous mutated genotype determines complete loss of function of enzymatic DPD effectiveness. DPYD*13, c.1679 T>G, and c.2846 A>T are missense mutations affecting the function of the protein, strongly related with fluoropyrimidine-induced adverse events: DPYD*13, c.1679 T>G induces the aminoacid change Ile560Ser in a DPD flavine binding domain; the non-synonymous variant c.2846 A>T, determining the Asp949Val aminoacid change near a DPD iron-sulfur motif.…”