Dan Rosmarin1, Claire Palles2, Alistair Pagnamenta3, Kulvinder Kaur3, Guillermo Pita4, Miguel Martin5, Enric Domingo6, Angela Jones2, Kimberley Howarth2, Luke Freeman-Mills2, Elaine Johnstone7, Haitao Wang7, Sharon Love8, Claire Scudder9, Patrick Julier9, Ceres Fernández-Rozadilla2, Clara Ruiz-Ponte10, Angel Carracedo10, Sergi Castellvi-Bel11, Antoni Castells12, Anna Gonzalez-Neira4, Jenny Taylor3, Rachel Kerr7, David Kerr13, Ian Tomlinson6. 1. Molecular and Population Genetics Laboratory, Oxford, UK Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK. 2. Molecular and Population Genetics Laboratory, Oxford, UK. 3. Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK. 4. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, Madrid, Spain. 5. Department of Medical Oncology, Instituto de Investigacion Sanitaria Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain. 6. Molecular and Population Genetics Laboratory, Oxford, UK Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK. 7. Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK. 8. Centre for Statistics in Medicine, University of Oxford, Botnar Research Centre, Oxford, UK. 9. OCTO, University of Oxford, Old Road Campus Research Building, Oxford, UK. 10. Galician Public Foundation of Genomic Medicine (FPGMX), CIBERER, Genomics Medicine Group, Hospital Clinico, University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain. 11. Genetic Susceptibility to Colorectal Cancer Group, Gastrointestinal & Pancreatic Oncology Team, IDIBAPS/CIBERehd/Hospital Clínic, Centre Esther Koplowitz (CEK), Barcelona, Spain. 12. Institute of Digestive and Metabolic Diseases, Hospital Clínic, Barcelona, Spain. 13. Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.
Abstract
OBJECTIVE: Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS). DESIGN: We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial. RESULTS: We identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10(-6)) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10(-5)). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10(-8)). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10(-6)). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5'VNTR 2R/3R and 3'UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression. CONCLUSIONS: DPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE:Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FUtoxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS). DESIGN: We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial. RESULTS: We identified the first common DPYD polymorphisms to be consistently associated with capecitabinetoxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10(-6)) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10(-5)). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10(-8)). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabinetoxicity (TAF=0.532, OR=1.59, p=5.28×10(-6)). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabinetoxicity and the supposedly functional TYMS variants, 5'VNTR 2R/3R and 3'UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression. CONCLUSIONS:DPYD harbours rare and common capecitabinetoxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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Keywords:
Cancer; Cancer Genetics; Chemotherapy; Pharmacogenetics
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