State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
School of Public Health, Sun Yat-sen University, Guangzhou, China.
Cancer Res Treat. 2021 Jul;53(3):724-732. doi: 10.4143/crt.2020.457. Epub 2020 Dec 2.
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.
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.
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.
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.
卡培他滨是一种广泛应用于结肠癌治疗的氟尿嘧啶口服前体药物，已知其可引起手足综合征（HFS）。作为卡培他滨的靶酶，胸苷酸合成酶（TYMS）在 5-氟尿嘧啶代谢中起着关键作用，并与卡培他滨引起的一些副作用有关。本研究旨在确定中国结直肠癌患者卡培他滨诱导的 HFS（CAP-HFS）的可能遗传预测因子。
对 288 名极端表型 HFS 患者（包括 144 例严重或早期（前 2 个周期）中度 HFS 极端病例和 144 例无报道 HFS 的极端对照）的 TYMS 全长外显子进行测序。采用加性模型的逻辑回归分析多态性与 CAP-HFS 之间的关系。
我们发现了一种新的风险突变（c.1A>G，chr18:657743），与治疗第一周期受影响的严重 HFS 极端病例相关。此外，我们还鉴定了三个新变体，rs3786362、rs699517、rs2790，以及两个先前报道的变体 5'VNTR 2R/3R 和 3'-非翻译区 6-bp ins-del，它们与 CAP-HFS 显著相关（p<0.05）。 体外分析表明，TYMS 区域这些多态性对 HFS 发展的影响可能不仅限于 TYMS 表达的调节，还可能通过对 ENOSF1 表达的间接影响来调节 TYMS 催化活性。
本研究鉴定了与 CAP-HFS 显著相关的 TYMS 基因中的新多态性，它们可能作为 CAP-HFS 的有用遗传预测因子，并有助于阐明 HFS 的潜在机制。
