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New advances in DPYD genotype and risk of severe toxicity under capecitabine
BACKGROUND: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421769/ https://www.ncbi.nlm.nih.gov/pubmed/28481884 http://dx.doi.org/10.1371/journal.pone.0175998 |
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author | Etienne-Grimaldi, Marie-Christine Boyer, Jean-Christophe Beroud, Christophe Mbatchi, Litaty van Kuilenburg, André Bobin-Dubigeon, Christine Thomas, Fabienne Chatelut, Etienne Merlin, Jean-Louis Pinguet, Frédéric Ferrand, Christophe Meijer, Judith Evrard, Alexandre Llorca, Laurence Romieu, Gilles Follana, Philippe Bachelot, Thomas Chaigneau, Loic Pivot, Xavier Dieras, Véronique Largillier, Rémy Mousseau, Mireille Goncalves, Anthony Roché, Henri Bonneterre, Jacques Servent, Véronique Dohollou, Nadine Château, Yann Chamorey, Emmanuel Desvignes, Jean-Pierre Salgado, David Ferrero, Jean-Marc Milano, Gérard |
author_facet | Etienne-Grimaldi, Marie-Christine Boyer, Jean-Christophe Beroud, Christophe Mbatchi, Litaty van Kuilenburg, André Bobin-Dubigeon, Christine Thomas, Fabienne Chatelut, Etienne Merlin, Jean-Louis Pinguet, Frédéric Ferrand, Christophe Meijer, Judith Evrard, Alexandre Llorca, Laurence Romieu, Gilles Follana, Philippe Bachelot, Thomas Chaigneau, Loic Pivot, Xavier Dieras, Véronique Largillier, Rémy Mousseau, Mireille Goncalves, Anthony Roché, Henri Bonneterre, Jacques Servent, Véronique Dohollou, Nadine Château, Yann Chamorey, Emmanuel Desvignes, Jean-Pierre Salgado, David Ferrero, Jean-Marc Milano, Gérard |
author_sort | Etienne-Grimaldi, Marie-Christine |
collection | PubMed |
description | BACKGROUND: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. METHODS: Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3’UTR and 5’UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement. RESULTS: Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3–4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3–4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR. CONCLUSIONS: Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3–4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V. |
format | Online Article Text |
id | pubmed-5421769 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54217692017-05-14 New advances in DPYD genotype and risk of severe toxicity under capecitabine Etienne-Grimaldi, Marie-Christine Boyer, Jean-Christophe Beroud, Christophe Mbatchi, Litaty van Kuilenburg, André Bobin-Dubigeon, Christine Thomas, Fabienne Chatelut, Etienne Merlin, Jean-Louis Pinguet, Frédéric Ferrand, Christophe Meijer, Judith Evrard, Alexandre Llorca, Laurence Romieu, Gilles Follana, Philippe Bachelot, Thomas Chaigneau, Loic Pivot, Xavier Dieras, Véronique Largillier, Rémy Mousseau, Mireille Goncalves, Anthony Roché, Henri Bonneterre, Jacques Servent, Véronique Dohollou, Nadine Château, Yann Chamorey, Emmanuel Desvignes, Jean-Pierre Salgado, David Ferrero, Jean-Marc Milano, Gérard PLoS One Research Article BACKGROUND: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. METHODS: Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3’UTR and 5’UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement. RESULTS: Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3–4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3–4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR. CONCLUSIONS: Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3–4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V. Public Library of Science 2017-05-08 /pmc/articles/PMC5421769/ /pubmed/28481884 http://dx.doi.org/10.1371/journal.pone.0175998 Text en © 2017 Etienne-Grimaldi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Etienne-Grimaldi, Marie-Christine Boyer, Jean-Christophe Beroud, Christophe Mbatchi, Litaty van Kuilenburg, André Bobin-Dubigeon, Christine Thomas, Fabienne Chatelut, Etienne Merlin, Jean-Louis Pinguet, Frédéric Ferrand, Christophe Meijer, Judith Evrard, Alexandre Llorca, Laurence Romieu, Gilles Follana, Philippe Bachelot, Thomas Chaigneau, Loic Pivot, Xavier Dieras, Véronique Largillier, Rémy Mousseau, Mireille Goncalves, Anthony Roché, Henri Bonneterre, Jacques Servent, Véronique Dohollou, Nadine Château, Yann Chamorey, Emmanuel Desvignes, Jean-Pierre Salgado, David Ferrero, Jean-Marc Milano, Gérard New advances in DPYD genotype and risk of severe toxicity under capecitabine |
title | New advances in DPYD genotype and risk of severe toxicity under capecitabine |
title_full | New advances in DPYD genotype and risk of severe toxicity under capecitabine |
title_fullStr | New advances in DPYD genotype and risk of severe toxicity under capecitabine |
title_full_unstemmed | New advances in DPYD genotype and risk of severe toxicity under capecitabine |
title_short | New advances in DPYD genotype and risk of severe toxicity under capecitabine |
title_sort | new advances in dpyd genotype and risk of severe toxicity under capecitabine |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421769/ https://www.ncbi.nlm.nih.gov/pubmed/28481884 http://dx.doi.org/10.1371/journal.pone.0175998 |
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