An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities
Efficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are...
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/7/1497 |
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| author | Claire Palles Susan Fotheringham Laura Chegwidden Marie Lucas Rachel Kerr Guy Mozolowski Dan Rosmarin Jenny C. Taylor Ian Tomlinson David Kerr |
| author_facet | Claire Palles Susan Fotheringham Laura Chegwidden Marie Lucas Rachel Kerr Guy Mozolowski Dan Rosmarin Jenny C. Taylor Ian Tomlinson David Kerr |
| author_sort | Claire Palles |
| collection | DOAJ |
| description | Efficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are available to identify patients at high risk of severe adverse events (AEs). We previously reported associations between rs1213215, rs2612091, and NM_000110.3:c.1906-14763G>A (rs12022243) and capecitabine induced toxicity in clinical trial QUASAR 2. We also identified patients with DPD deficiency alleles NM_000110.3: c.1905+1G>A, NM_000110.3: c.2846C>T, NM_000110.3:c.1679T>G and NM_000110.3:c.1651G>A. We have now assessed the frequency of thirteen additional <i>DPYD</i> deficiency variants in 888 patients from the QUASAR 2 clinical trial. We also compared the area under the curve (AUC)—a measure of diagnostic accuracy—of the high-level evidence variants from the CPIC guidelines plus and minus additional <i>DPYD</i> deficiency variants and or common variants associated with 5-FU toxicity. Including additional <i>DPYD</i> deficiency variants retained good diagnostic accuracy for serious adverse events (AEs) and improved sensitivity for predicting grade 4 haematological toxicities (sensitivity 0.75, specificity 0.94) but the improvement in AUC for this toxicity was not significant. Larger datasets will be required to determine the benefit of including additional <i>DPYD</i> deficiency variants not observed here. Genotyping two common alleles statistically significantly improves AUC for prediction of risk of HFS and may be clinically useful (AUC difference 0.177, sensitivity 0.84, specificity 0.31). |
| first_indexed | 2024-03-10T12:55:45Z |
| format | Article |
| id | doaj.art-0b88da015cf04c9ca51a4e33d6363066 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T12:55:45Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0b88da015cf04c9ca51a4e33d63630662023-11-21T11:51:40ZengMDPI AGCancers2072-66942021-03-01137149710.3390/cancers13071497An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related ToxicitiesClaire Palles0Susan Fotheringham1Laura Chegwidden2Marie Lucas3Rachel Kerr4Guy Mozolowski5Dan Rosmarin6Jenny C. Taylor7Ian Tomlinson8David Kerr9Gastrointestinal Cancer Genetics, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UKOxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UKGastrointestinal Cancer Genetics, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UKWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKDepartment of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UKOxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UKWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKWellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UKCancer Genetics and Evolution Laboratory, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UKOxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UKEfficacy of 5-Fluorouracil (5-FU)-based chemotherapy is limited by significant toxicity. Tests based upon variants in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines with high level evidence of a link to dihydropyrimidine dehydrogenase (DPD) phenotype and 5-FU toxicity are available to identify patients at high risk of severe adverse events (AEs). We previously reported associations between rs1213215, rs2612091, and NM_000110.3:c.1906-14763G>A (rs12022243) and capecitabine induced toxicity in clinical trial QUASAR 2. We also identified patients with DPD deficiency alleles NM_000110.3: c.1905+1G>A, NM_000110.3: c.2846C>T, NM_000110.3:c.1679T>G and NM_000110.3:c.1651G>A. We have now assessed the frequency of thirteen additional <i>DPYD</i> deficiency variants in 888 patients from the QUASAR 2 clinical trial. We also compared the area under the curve (AUC)—a measure of diagnostic accuracy—of the high-level evidence variants from the CPIC guidelines plus and minus additional <i>DPYD</i> deficiency variants and or common variants associated with 5-FU toxicity. Including additional <i>DPYD</i> deficiency variants retained good diagnostic accuracy for serious adverse events (AEs) and improved sensitivity for predicting grade 4 haematological toxicities (sensitivity 0.75, specificity 0.94) but the improvement in AUC for this toxicity was not significant. Larger datasets will be required to determine the benefit of including additional <i>DPYD</i> deficiency variants not observed here. Genotyping two common alleles statistically significantly improves AUC for prediction of risk of HFS and may be clinically useful (AUC difference 0.177, sensitivity 0.84, specificity 0.31).https://www.mdpi.com/2072-6694/13/7/1497pharmacogeneticsdihydropyrimidine dehydrogenase5-FU |
| spellingShingle | Claire Palles Susan Fotheringham Laura Chegwidden Marie Lucas Rachel Kerr Guy Mozolowski Dan Rosmarin Jenny C. Taylor Ian Tomlinson David Kerr An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities Cancers pharmacogenetics dihydropyrimidine dehydrogenase 5-FU |
| title | An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities |
| title_full | An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities |
| title_fullStr | An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities |
| title_full_unstemmed | An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities |
| title_short | An Evaluation of the Diagnostic Accuracy of a Panel of Variants in <i>DPYD</i> and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities |
| title_sort | evaluation of the diagnostic accuracy of a panel of variants in i dpyd i and a single variant in enosf1 for predicting common capecitabine related toxicities |
| topic | pharmacogenetics dihydropyrimidine dehydrogenase 5-FU |
| url | https://www.mdpi.com/2072-6694/13/7/1497 |
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