PMID- 33805100 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210413 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 13 IP - 7 DP - 2021 Mar 24 TI - 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. LID - 10.3390/cancers13071497 [doi] LID - 1497 AB - 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). FAU - Palles, Claire AU - Palles C AUID- ORCID: 0000-0002-9670-2263 AD - Gastrointestinal Cancer Genetics, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. FAU - Fotheringham, Susan AU - Fotheringham S AUID- ORCID: 0000-0001-5440-8747 AD - Oxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UK. FAU - Chegwidden, Laura AU - Chegwidden L AUID- ORCID: 0000-0001-5041-8163 AD - Gastrointestinal Cancer Genetics, Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. FAU - Lucas, Marie AU - Lucas M AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. FAU - Kerr, Rachel AU - Kerr R AD - Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK. FAU - Mozolowski, Guy AU - Mozolowski G AD - Oxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UK. FAU - Rosmarin, Dan AU - Rosmarin D AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. FAU - Taylor, Jenny C AU - Taylor JC AD - Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. AD - Oxford and National Institute for Health Research Biomedical Research Centre, Unipart House Business Centre, Garsington Road, Oxford OX4 2PG, UK. FAU - Tomlinson, Ian AU - Tomlinson I AD - Cancer Genetics and Evolution Laboratory, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK. FAU - Kerr, David AU - Kerr D AD - Oxford Cancer Biomarkers, The Magdalen Centre, Oxford Science Park, Robert Robinson Avenue, Oxford OX4 4GA, UK. AD - Nuffield Division of Clinical and Laboratory Sciences, University of Oxford, Level 6, West Wing John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. LA - eng GR - not known/CRUK_/Cancer Research UK/United Kingdom GR - not known/Roche/ GR - not applicable/Oxford Cancer Biomarkers/ GR - not known/NIHR Oxford Biomedical Research Centre/ PT - Journal Article DEP - 20210324 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC8037940 OTO - NOTNLM OT - 5-FU OT - dihydropyrimidine dehydrogenase OT - pharmacogenetics COIS- S.F., G.M., L.C., R.K. and J.C.T. have nothing to disclose. C.P. reports grants and personal fees from Oxford Cancer Biomarkers Ltd., during the conduct of the study. M.L. reports grants and personal fees from Oxford Cancer Biomarkers Ltd., during the conduct of the study. D.K. reports personal fees from Oxford Cancer Biomarkers Ltd., non-financial support from My-BioMed Biotechnology Co., Ltd., China, during the conduct of the study; grants from Bayer, outside the submitted work. Other authors declare no conflict of interest. EDAT- 2021/04/04 06:00 MHDA- 2021/04/04 06:01 PMCR- 2021/03/24 CRDT- 2021/04/03 01:19 PHST- 2021/01/22 00:00 [received] PHST- 2021/03/19 00:00 [revised] PHST- 2021/03/22 00:00 [accepted] PHST- 2021/04/03 01:19 [entrez] PHST- 2021/04/04 06:00 [pubmed] PHST- 2021/04/04 06:01 [medline] PHST- 2021/03/24 00:00 [pmc-release] AID - cancers13071497 [pii] AID - cancers-13-01497 [pii] AID - 10.3390/cancers13071497 [doi] PST - epublish SO - Cancers (Basel). 2021 Mar 24;13(7):1497. doi: 10.3390/cancers13071497.