DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and c.2846A>T: a comprehensive analysis in 1254 patients

Abstract

Dihydropyrimidine dehydrogenase (DPYD) is a highly polymorphic gene and classic deficient variants (i.e., c.1236G>A/HapB3, c.1679T>G, c.1905+1G>A and c.2846A>T) are characterized by impaired enzyme activity and risk of severe adverse drug reactions (ADRs) in patients treated with fluoropyrimidines. The identification of poor metabolizers by pre-emptive DPYD screening may reduce the rate of ADRs but many patients with wild-type genotype for classic variants may still display ADRs. Therefore, the search for additional DPYD polymorphisms associated with ADRs may improve the safety of treatment with fluoropyrimidines. This study included 1254 patients treated with fluoropyrimidine-containing regimens and divided into cohort 1, which included 982 subjects suffering from gastrointestinal G≥2 and/or hematological G≥3 ADRs, and cohort 2 (control group), which comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment. Both groups were screened for DPYD variants c.496A>G, c.1236G>A/HapB3, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c.1905 + 1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with toxicity. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2, while c.1905+1G>A and c.2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A/HapB3 were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c.2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p < 0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p = 0.06). In conclusion, c.2194G>A is associated with clinically-relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T variants and should be evaluated pre-emptively to reduce the risk of fluoropyrimidine-associated ADRs.

Dihydropyrimidine dehydrogenase deficiency in patients with severe toxicity after 5-fluorouracil: a retrospective single-center study

“…Additionally, 6 patients with a single DPYD*9A mutation, 14 with a single DPYD*5 mutation and 4 with a single DPYD*6 mutation were all documented to have severe toxicity. A recent large study of 1254 patients also found a significant association between DPYD*6 and severe 5-FU toxicity [ 20 ]. We also recorded 31 patients who had more than one DPYD gene variant.…”

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

“…The metabolism of fluoropyrimidine involves enzymes with different intermediate metabolites, prevalently depending on the key enzyme DPD, that metabolize >80% administered 5-FU or capecitabine dose into 5-fluoro-5,6-dihydrouracil (5-FDHU). 27 In the event of DPD inactivation or reduced effectiveness, the 5-FU amount for activation of anabolic pathway increases, inducing adverse effects.…”

“…The authors suggested more investigation for c.1236G>A and c.2846A>T carriers and adequate dose modulation 50% vs 25%. 1896T>C, and c.2194G>A variants were detected in a population of 982 patients who experienced ≥G2 gastrointestinal and/or ≥G3 hematological adverse events, and in a cohort of 272 patients not requiring reduction of drug dose, treatment delay, or discontinuation; while c.1905+1G>A and c.2846A>T were reported only in the cohort of patients experiencing LT 27. DPYD c.1679T>G In an univariate analysis, DPYD*2A c.1905+1G>A, c.2846A>T, and c.2194G>A alleles were reported as significantly correlated with hematological and gastrointestinal adverse events (P<0.05); c.496A>G variant was associated with neutropenia (P=0.06).…”

Management of patients with early-stage colon cancer: guidelines of the Italian Medical Oncology Association

“…Based on the recent recommendation of the (European Medicines Agency (EMA); EMA/125891/2020) and AIFA (Italian Medicines Agency; AIFA 2020.05.25) Pharmacovigilance Risk Assessment Committee, all patients who are candidates for fluoropyrimidine treatment should be tested for dihydropyrimidine dehydrogenase (DPYD) to prevent potentially serious adverse events. The working group recommends the analysis of the following mutations: c.1236G>A (c.1129-5923C>G), c.1679T>G, c.1905+1G>A and c.2846A>T. 91 Furthermore, it may be useful to consider additional variants such as c.2194G>A in case of toxicity during treatment [92][93][94][95][96] (table 3).…”