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

Abstract

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.

• Authors: Si-Qi Dong, Tong-Min Wang, Jiang-Bo Zhang, Yong-Qiao He, Wen-Qiong Xue, Zi-Yi Wu, Da-Wei Yang, Lian-Jing Cao, Jing-Wen Huang, Xi-Zhao Li, Pei-Fen Zhang, Xiao-Hui Zheng, Wei-Hua Jia
• Journal: Cancer research and treatment (Cancer Res Treat) Vol. 53 Issue 3 Pg. 724-732 (Jul 2021) ISSN: 2005-9256 [Electronic] Korea (South)
• PMID: 33285053 (Publication Type: Journal Article, Observational Study)

Chemical References

• 3' Untranslated Regions
• Antimetabolites, Antineoplastic
• Capecitabine
• TYMS protein, human
• Thymidylate Synthase
• ENOSF1 protein, human
• Hydro-Lyases

Topics

• 3' Untranslated Regions (genetics)
• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (adverse effects)
• Asian People (genetics)
• Capecitabine (adverse effects)
• Colorectal Neoplasms (drug therapy, genetics)
• Female
• Genetic Predisposition to Disease
• Hand-Foot Syndrome (epidemiology, genetics)
• Humans
• Hydro-Lyases (metabolism)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Thymidylate Synthase (genetics, metabolism)