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Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer

PURPOSE: Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some...

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Autores principales: Dong, Si-Qi, Wang, Tong-Min, Zhang, Jiang-Bo, He, Yong-Qiao, Xue, Wen-Qiong, Wu, Zi-Yi, Yang, Da-Wei, Cao, Lian-Jing, Huang, Jing-Wen, Li, Xi-Zhao, Zhang, Pei-Fen, Zheng, Xiao-Hui, Jia, Wei-Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Cancer Association 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291172/
https://www.ncbi.nlm.nih.gov/pubmed/33285053
http://dx.doi.org/10.4143/crt.2020.457
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author Dong, Si-Qi
Wang, Tong-Min
Zhang, Jiang-Bo
He, Yong-Qiao
Xue, Wen-Qiong
Wu, Zi-Yi
Yang, Da-Wei
Cao, Lian-Jing
Huang, Jing-Wen
Li, Xi-Zhao
Zhang, Pei-Fen
Zheng, Xiao-Hui
Jia, Wei-Hua
author_facet Dong, Si-Qi
Wang, Tong-Min
Zhang, Jiang-Bo
He, Yong-Qiao
Xue, Wen-Qiong
Wu, Zi-Yi
Yang, Da-Wei
Cao, Lian-Jing
Huang, Jing-Wen
Li, Xi-Zhao
Zhang, Pei-Fen
Zheng, Xiao-Hui
Jia, Wei-Hua
author_sort Dong, Si-Qi
collection PubMed
description PURPOSE: Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients. MATERIALS AND METHODS: Whole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model. RESULTS: We identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5’VNTR 2R/3R and 3′-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression. CONCLUSION: This study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.
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spelling pubmed-82911722021-08-04 Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer Dong, Si-Qi Wang, Tong-Min Zhang, Jiang-Bo He, Yong-Qiao Xue, Wen-Qiong Wu, Zi-Yi Yang, Da-Wei Cao, Lian-Jing Huang, Jing-Wen Li, Xi-Zhao Zhang, Pei-Fen Zheng, Xiao-Hui Jia, Wei-Hua Cancer Res Treat Original Article PURPOSE: Capecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients. MATERIALS AND METHODS: Whole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model. RESULTS: We identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5’VNTR 2R/3R and 3′-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression. CONCLUSION: This study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS. Korean Cancer Association 2021-07 2020-12-02 /pmc/articles/PMC8291172/ /pubmed/33285053 http://dx.doi.org/10.4143/crt.2020.457 Text en Copyright © 2021 by the Korean Cancer Association https://creativecommons.org/licenses/by-nc/4.0/This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Dong, Si-Qi
Wang, Tong-Min
Zhang, Jiang-Bo
He, Yong-Qiao
Xue, Wen-Qiong
Wu, Zi-Yi
Yang, Da-Wei
Cao, Lian-Jing
Huang, Jing-Wen
Li, Xi-Zhao
Zhang, Pei-Fen
Zheng, Xiao-Hui
Jia, Wei-Hua
Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer
title Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer
title_full Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer
title_fullStr Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer
title_full_unstemmed Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer
title_short Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer
title_sort polymorphisms in tyms for prediction of capecitabine-induced hand-foot syndrome in chinese patients with colorectal cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291172/
https://www.ncbi.nlm.nih.gov/pubmed/33285053
http://dx.doi.org/10.4143/crt.2020.457
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