Integrative Bioinformatics Analysis: Unraveling Variant Signatures and Single-Nucleotide Polymorphism Markers Associated with 5-FU-Based Chemotherapy Resistance in Colorectal Cancer Patients.

IF 1.6 Q4 ONCOLOGY Journal of Gastrointestinal Cancer Pub Date : 2024-12-01 Epub Date: 2024-09-06 DOI:10.1007/s12029-024-01102-x
Masomeh Askari, Ebrahim Mirzaei, Leila Navapour, Mina Karimpour, Leili Rejali, Somayeh Sarirchi, Ehsan Nazemalhosseini-Mojarad, Stefania Nobili, Claudia Cava, Amir Sadeghi, Nayeralsadat Fatemi
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Abstract

Background: Drug resistance in colorectal cancer (CRC) is modulated by multiple molecular factors, which can be ascertained through genetic investigation. Single nucleotide polymorphisms (SNPs) within key genes have the potential to impair the efficacy of chemotherapeutic agents such as 5-fluorouracil (5-FU). Therefore, the identification of SNPs linked to drug resistance can significantly contribute to the advancement of tailored therapeutic approaches and the enhancement of treatment outcomes in patients with CRC.

Material and method: To identify dysregulated genes in 5-FU-based chemotherapy responder or non-responder CRC patients, a meta-analysis was performed. Next, the protein-protein interaction (PPI) network of the identified genes was analyzed using the STRING database. The most significant module was chosen for further analysis. In addition, a literature review was conducted to identify drug resistance-related genes. Enrichment analysis was conducted to validate the main module genes and the genes identified from the literature review. The associations between SNPs and drug resistance were investigated, and the consequences of missense variants were assessed using in silico tools.

Result: The meta-analysis identified 796 dysregulated genes. Then, to conduct PPI analysis and enrichment analysis, we were able to discover 23 genes that are intricately involved in the cell cycle pathway. Consequently, these 23 genes were chosen for SNP analysis. By using the dbSNP database and ANNOVAR, we successfully detected and labeled SNPs in these specific genes. Additionally, after careful exclusion of SNPs with allele frequencies below 0.01, we evaluated 6 SNPs from the HDAC1, MCM2, CDK1, BUB1B, CDC14B, and CCNE1 genes using 8 bioinformatics tools. Therefore, these SNPs were identified as potentially harmful by multiple computational tools. Specifically, rs199958833 in CDK1 (Val124Gly) was predicted to be damaging by all tools used. Our analysis strongly indicates that this specific SNP could negatively affect the stability and functionality of the CDK1 protein.

Conclusion: Based on our current understanding, the evaluation of CDK1 polymorphisms in the context of drug resistance in CRC has yet to be undertaken. In this investigation, we showed that rs199958833 variant in the CDK1 gene may favor resistance to 5-FU-based chemotherapy. However, these findings need validation in an independent cohort of patients.

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综合生物信息学分析:揭示结直肠癌患者与 5-FU 化疗耐药性相关的变异特征和单核苷酸多态性标记物
背景:结直肠癌(CRC)的耐药性受多种分子因素的影响,而这些因素可通过基因研究加以确定。关键基因中的单核苷酸多态性(SNPs)有可能损害 5-氟尿嘧啶(5-FU)等化疗药物的疗效。因此,鉴定与耐药性相关的SNPs可极大地促进定制治疗方法的发展,并提高CRC患者的治疗效果:为了确定5-FU化疗应答或非应答CRC患者的失调基因,我们进行了一项荟萃分析。然后,利用 STRING 数据库分析了已识别基因的蛋白-蛋白相互作用(PPI)网络。选择最重要的模块进行进一步分析。此外,还进行了文献综述,以确定耐药性相关基因。进行了富集分析以验证主要模块基因和文献综述中发现的基因。研究人员还调查了 SNP 与耐药性之间的关联,并使用硅学工具评估了错义变异的后果:结果:荟萃分析确定了 796 个失调基因。然后,通过PPI分析和富集分析,我们发现了23个与细胞周期通路密切相关的基因。因此,我们选择了这 23 个基因进行 SNP 分析。通过使用 dbSNP 数据库和 ANNOVAR,我们成功地检测并标记了这些特定基因中的 SNP。此外,在仔细排除等位基因频率低于 0.01 的 SNP 后,我们使用 8 种生物信息学工具评估了 HDAC1、MCM2、CDK1、BUB1B、CDC14B 和 CCNE1 基因中的 6 个 SNP。因此,这些 SNP 被多种计算工具确定为潜在的有害基因。具体来说,CDK1(Val124Gly)中的 rs199958833 被所有使用的工具预测为有害。我们的分析强烈表明,这个特定的 SNP 可能会对 CDK1 蛋白的稳定性和功能性产生负面影响:根据我们目前的了解,CDK1 多态性对 CRC 耐药性的影响尚未进行评估。在这项研究中,我们发现 CDK1 基因中的 rs199958833 变异可能会增加对以 5-FU 为基础的化疗的耐药性。然而,这些发现还需要在独立的患者队列中进行验证。
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来源期刊
CiteScore
3.80
自引率
0.00%
发文量
121
期刊介绍: The Journal of Gastrointestinal Cancer is a multidisciplinary medium for the publication of novel research pertaining to cancers arising from the gastrointestinal tract.The journal is dedicated to the most rapid publication possible.The journal publishes papers in all relevant fields, emphasizing those studies that are helpful in understanding and treating cancers affecting the esophagus, stomach, liver, gallbladder and biliary tree, pancreas, small bowel, large bowel, rectum, and anus. In addition, the Journal of Gastrointestinal Cancer publishes basic and translational scientific information from studies providing insight into the etiology and progression of cancers affecting these organs. New insights are provided from diverse areas of research such as studies exploring pre-neoplastic states, risk factors, epidemiology, genetics, preclinical therapeutics, surgery, radiation therapy, novel medical therapeutics, clinical trials, and outcome studies.In addition to reports of original clinical and experimental studies, the journal also publishes: case reports, state-of-the-art reviews on topics of immediate interest or importance; invited articles analyzing particular areas of pancreatic research and knowledge; perspectives in which critical evaluation and conflicting opinions about current topics may be expressed; meeting highlights that summarize important points presented at recent meetings; abstracts of symposia and conferences; book reviews; hypotheses; Letters to the Editors; and other items of special interest, including:Complex Cases in GI Oncology:  This is a new initiative to provide a forum to review and discuss the history and management of complex and involved gastrointestinal oncology cases. The format will be similar to a teaching case conference where a case vignette is presented and is followed by a series of questions and discussion points. A brief reference list supporting the points made in discussion would be expected.
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