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A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS.
Gut 2015; 64(1):111-20Gut

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.

Authors+Show Affiliations

Molecular and Population Genetics Laboratory, Oxford, UK Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK.Molecular and Population Genetics Laboratory, Oxford, UK.Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, Madrid, Spain.Department of Medical Oncology, Instituto de Investigacion Sanitaria Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain.Molecular and Population Genetics Laboratory, Oxford, UK Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.Molecular and Population Genetics Laboratory, Oxford, UK.Molecular and Population Genetics Laboratory, Oxford, UK.Molecular and Population Genetics Laboratory, Oxford, UK.Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK.Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK.Centre for Statistics in Medicine, University of Oxford, Botnar Research Centre, Oxford, UK.OCTO, University of Oxford, Old Road Campus Research Building, Oxford, UK.OCTO, University of Oxford, Old Road Campus Research Building, Oxford, UK.Molecular and Population Genetics Laboratory, Oxford, UK.Galician Public Foundation of Genomic Medicine (FPGMX), CIBERER, Genomics Medicine Group, Hospital Clinico, University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain.Galician Public Foundation of Genomic Medicine (FPGMX), CIBERER, Genomics Medicine Group, Hospital Clinico, University of Santiago de Compostela, Santiago de Compostela, Galicia, Spain.Genetic Susceptibility to Colorectal Cancer Group, Gastrointestinal & Pancreatic Oncology Team, IDIBAPS/CIBERehd/Hospital Clínic, Centre Esther Koplowitz (CEK), Barcelona, Spain.Institute of Digestive and Metabolic Diseases, Hospital Clínic, Barcelona, Spain.Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, Madrid, Spain.Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, UK.Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK.Molecular and Population Genetics Laboratory, Oxford, UK Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Oxford, UK.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24647007

Citation

Rosmarin, Dan, et al. "A Candidate Gene Study of Capecitabine-related Toxicity in Colorectal Cancer Identifies New Toxicity Variants at DPYD and a Putative Role for ENOSF1 Rather Than TYMS." Gut, vol. 64, no. 1, 2015, pp. 111-20.
Rosmarin D, Palles C, Pagnamenta A, et al. A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut. 2015;64(1):111-20.
Rosmarin, D., Palles, C., Pagnamenta, A., Kaur, K., Pita, G., Martin, M., ... Tomlinson, I. (2015). A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. Gut, 64(1), pp. 111-20. doi:10.1136/gutjnl-2013-306571.
Rosmarin D, et al. A Candidate Gene Study of Capecitabine-related Toxicity in Colorectal Cancer Identifies New Toxicity Variants at DPYD and a Putative Role for ENOSF1 Rather Than TYMS. Gut. 2015;64(1):111-20. PubMed PMID: 24647007.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS. AU - Rosmarin,Dan, AU - Palles,Claire, AU - Pagnamenta,Alistair, AU - Kaur,Kulvinder, AU - Pita,Guillermo, AU - Martin,Miguel, AU - Domingo,Enric, AU - Jones,Angela, AU - Howarth,Kimberley, AU - Freeman-Mills,Luke, AU - Johnstone,Elaine, AU - Wang,Haitao, AU - Love,Sharon, AU - Scudder,Claire, AU - Julier,Patrick, AU - Fernández-Rozadilla,Ceres, AU - Ruiz-Ponte,Clara, AU - Carracedo,Angel, AU - Castellvi-Bel,Sergi, AU - Castells,Antoni, AU - Gonzalez-Neira,Anna, AU - Taylor,Jenny, AU - Kerr,Rachel, AU - Kerr,David, AU - Tomlinson,Ian, Y1 - 2014/03/19/ PY - 2014/3/21/entrez PY - 2014/3/22/pubmed PY - 2015/2/19/medline KW - Cancer KW - Cancer Genetics KW - Chemotherapy KW - Pharmacogenetics SP - 111 EP - 20 JF - Gut JO - Gut VL - 64 IS - 1 N2 - 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. SN - 1468-3288 UR - https://www.unboundmedicine.com/medline/citation/24647007/A_candidate_gene_study_of_capecitabine_related_toxicity_in_colorectal_cancer_identifies_new_toxicity_variants_at_DPYD_and_a_putative_role_for_ENOSF1_rather_than_TYMS_ L2 - http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=24647007 DB - PRIME DP - Unbound Medicine ER -