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Open AccessArticle

An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities

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Gastrointestinal Cancer Genetics, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
2
Oxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UK
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Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
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Oxford and National Institute for Health Research Biomedical Research Centre, Unipart House Business Centre, Garsington Road, Oxford OX4 2PG, UK
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Cancer Genetics and Evolution Laboratory, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK
7
Nuffield Division of Clinical and Laboratory Sciences, University of Oxford, Level 6, West Wing John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Godefridus J. (Frits) Peters
Cancers 2021, 13(7), 1497; https://doi.org/10.3390/cancers13071497
Received: 22 January 2021 / Revised: 19 March 2021 / Accepted: 22 March 2021 / Published: 24 March 2021
(This article belongs to the Special Issue Molecular Biomarkers in Colorectal Cancer)
5-Fluorouracil (5-FU) is a chemotherapy drug that can cause severe toxicity in some patients. A protein, an action molecule in our cells, called dihydropyrimidine dehydrogenase, or DPD for short, is important in clearing 5-FU from the body. Some people have versions of DPD that do not clear 5-FU very well. This causes active drug to stay in the body too long, causing toxicities such as diarrhoea or low levels of blood cells important for fighting infections. Current guidelines identify four sequence changes in the gene that encodes DPD with high level evidence of an impact on protein activity. Our study aims to calculate the frequency of a set of variants identified in patients with DPD deficiency in patients that were part of a clinical trial called QUASAR 2. We go on to test how well the DPD deficiency variants and a set of common variants previously shown to be associated with 5-FU toxicity can predict a person’s risk of 5-Fluorouracil induced toxicity. Our research is important for working out the best way to identify patients at risk of toxicity so high risk patients can be given lower doses of 5-Fluorouracil or be treated with a different drug all together.
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 DPYD 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 DPYD deficiency variants and or common variants associated with 5-FU toxicity. Including additional DPYD 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 DPYD 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). View Full-Text
Keywords: pharmacogenetics; dihydropyrimidine dehydrogenase; 5-FU pharmacogenetics; dihydropyrimidine dehydrogenase; 5-FU
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MDPI and ACS Style

Palles, C.; Fotheringham, S.; Chegwidden, L.; Lucas, M.; Kerr, R.; Mozolowski, G.; Rosmarin, D.; Taylor, J.C.; Tomlinson, I.; Kerr, D. An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities. Cancers 2021, 13, 1497. https://doi.org/10.3390/cancers13071497

AMA Style

Palles C, Fotheringham S, Chegwidden L, Lucas M, Kerr R, Mozolowski G, Rosmarin D, Taylor JC, Tomlinson I, Kerr D. An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities. Cancers. 2021; 13(7):1497. https://doi.org/10.3390/cancers13071497

Chicago/Turabian Style

Palles, Claire; Fotheringham, Susan; Chegwidden, Laura; Lucas, Marie; Kerr, Rachel; Mozolowski, Guy; Rosmarin, Dan; Taylor, Jenny C.; Tomlinson, Ian; Kerr, David. 2021. "An Evaluation of the Diagnostic Accuracy of a Panel of Variants in DPYD and a Single Variant in ENOSF1 for Predicting Common Capecitabine Related Toxicities" Cancers 13, no. 7: 1497. https://doi.org/10.3390/cancers13071497

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