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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.
Highlights
Fluoropyrimidines are the most widely used chemotherapeutic agents for the treatment of many solid tumors, including gastrointestinal, head and neck, pancreas, and Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the article breast cancers [1]
Fluoropyrimidines are associated with adverse drug reactions (ADRs), including gastrointestinal and hematological toxicities and hand-foot syndrome (HFS), which may be life-threatening [2]
The same Dihydropyrimidine dehydrogenase (DPYD) variants examined in cohort 1 were examined in a control population of 272 subjects displaying optimal tolerability to treatment to better define which DPYD variants are associated with clinically-relevant ADRs
Summary
Extended author information available on the last page of the article breast cancers [1]. 5-fluorouracil (5-FU) and its prodrug capecitabine are the backbone of many combination chemotherapy regimens. Despite their clinical benefit, fluoropyrimidines are associated with adverse drug reactions (ADRs), including gastrointestinal and hematological toxicities and hand-foot syndrome (HFS), which may be life-threatening [2]. Fluoropyrimidine metabolism involves numerous enzymes with many intermediate metabolites, but the DPYD*6 plays an important role in fluoropyrimidine toxicity in addition to DPYD*2A and
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