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Purpose <p>Among cancer patients treated with fluoropyrimidine chemotherapeutics, approximately 30% of individuals experience severe fluoropyrimidine-associated toxicity. Dihydropyrimidine dehydrogenase (DPD, gene <i>DPYD</i>) is the main enzyme responsible for fluoropyrimidine metabolism; genetic variation in the <i>DPYD</i> gene that reduce enzyme function may contribute to increased risk for fluoropyrimidine toxicity. Routine pre-emptive genotype testing and dose adjustments for c.1905 + 1G &gt; A (rs3918290, <i>DPYD</i>*2A), c.2846&#xa0;A &gt; T (rs67376798, p.D949V), c.1679T &gt; G (rs55886062, <i>DPYD</i>*13, p.I560S), and c.1129–5923&#xa0;C &gt; G (rs75017182, HapB3) according to the guidelines established by international consortia predicts 20–30% of toxicity cases. However, the majority of severe adverse events are not captured by the currently recommended panel of four variants. There is a paucity of data regarding novel and rare (minor allelic frequency &lt; 1%) <i>DPYD</i> genetic variants associated with chemotherapy-related toxicity.</p> Methods <p>Whole-exome next generation sequencing was carried out in a retrospective study of 334 fluoropyrimidine-treated cancer patients to identify <i>DPYD</i> variants and potential association with severe toxicity.</p> Results <p>We identified 10 rare <i>DPYD</i> variants among 334 fluoropyrimidine-treated cancer patients that were wildtype for the pre-emptively tested variants. Four nonsynonymous rare <i>DPYD</i> variants, c.257&#xa0;C &gt; T (rs568132506, p.P86L), c.601&#xa0;A &gt; C (rs72549308, p.S201R), c.1850&#xa0;C &gt; T (rs753707032, p.T617M), and c.2324T &gt; G (rs200643089, p.L775W), were found in patients that experienced severe toxicity.</p> Conclusions <p>The discovery of rare <i>DPYD</i> variants followed by functional characterization may aid in further optimization of fluoropyrimidine dosing.</p>

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Potential clinical relevance of rare dihydropyrimidine dehydrogenase genetic variants identified using whole-exome NextGen sequencing in cancer patients with severe fluoropyrimidine toxicity

  • 期刊论文

  • 发表日期：

    2025年12月4日

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  • Elizabeth Cui,
  • Samantha Medwid,
  • Ute I. Schwarz,
  • Richard B. Kim

摘要

Purpose

Among cancer patients treated with fluoropyrimidine chemotherapeutics, approximately 30% of individuals experience severe fluoropyrimidine-associated toxicity. Dihydropyrimidine dehydrogenase (DPD, gene DPYD) is the main enzyme responsible for fluoropyrimidine metabolism; genetic variation in the DPYD gene that reduce enzyme function may contribute to increased risk for fluoropyrimidine toxicity. Routine pre-emptive genotype testing and dose adjustments for c.1905 + 1G > A (rs3918290, DPYD*2A), c.2846 A > T (rs67376798, p.D949V), c.1679T > G (rs55886062, DPYD*13, p.I560S), and c.1129–5923 C > G (rs75017182, HapB3) according to the guidelines established by international consortia predicts 20–30% of toxicity cases. However, the majority of severe adverse events are not captured by the currently recommended panel of four variants. There is a paucity of data regarding novel and rare (minor allelic frequency < 1%) DPYD genetic variants associated with chemotherapy-related toxicity.

Methods

Whole-exome next generation sequencing was carried out in a retrospective study of 334 fluoropyrimidine-treated cancer patients to identify DPYD variants and potential association with severe toxicity.

Results

We identified 10 rare DPYD variants among 334 fluoropyrimidine-treated cancer patients that were wildtype for the pre-emptively tested variants. Four nonsynonymous rare DPYD variants, c.257 C > T (rs568132506, p.P86L), c.601 A > C (rs72549308, p.S201R), c.1850 C > T (rs753707032, p.T617M), and c.2324T > G (rs200643089, p.L775W), were found in patients that experienced severe toxicity.

Conclusions

The discovery of rare DPYD variants followed by functional characterization may aid in further optimization of fluoropyrimidine dosing.