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Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
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The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy.

Francesco Iachetta1, Candida Bonelli2, Alessandra Romagnani2

  • 1Medical Oncology Unit, Clinical Cancer Centre, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy. francesco.iachetta@ausl.re.it.

British Journal of Cancer
|March 13, 2019
PubMed
Abstract

Insights

Identifying DPYD gene variants is crucial for preventing fluoropyrimidine toxicity. Additional DPYD polymorphisms, beyond DPYD*2A, are associated with severe toxicities, aiding in personalized chemotherapy.

Area of Science:

  • Pharmacogenomics
  • Oncology
  • Clinical Chemistry

Background:

  • Dihydropyrimidine dehydrogenase (DPD) deficiency, caused by DPYD gene variants, leads to severe toxicities with standard fluoropyrimidine chemotherapy.
  • The optimal panel of DPYD single-nucleotide polymorphisms (SNPs) for predicting toxicity remains undefined.

Purpose of the Study:

  • To investigate the clinical utility of additional DPYD SNPs beyond DPYD*2A in predicting fluoropyrimidine-induced toxicities.
  • To identify specific DPYD variants associated with severe adverse events in patients undergoing fluoropyrimidine-based chemotherapy.

Main Methods:

  • A case-control study screened 1827 patients for DPD deficiency from 2011 to 2016.
  • Patients with DPYD*2A and those who developed severe toxicities (≥G3) were compared to controls with no or mild toxicities.
  • Additional SNPs (c.2846A>T, c.1679T>G, c.2194G>A) were genotyped and analyzed for association with toxicity.

Main Results:

  • DPYD*2A was identified in 1.7% of patients.
  • Among 146 cases with severe toxicity and 220 controls, 53 patients carried additional SNPs (35 cases, 18 controls; p < 0.0001).
  • The c.2194G>A SNP (12.5% frequency) correlated with neutropenia, while c.2846A>T and c.1679T>G were linked to various toxicities.

Conclusions:

  • Incorporating additional DPYD polymorphisms into screening panels can improve the prevention of fluoropyrimidine-related toxicities.
  • The c.2194G>A SNP is a frequent variant associated with neutropenia, highlighting its clinical relevance.

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