Curtis Aaron A, Yu Yajun, Carey Megan, Parfrey Patrick, Yilmaz Yildiz E, Savas Sevtap
Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, NL, Canada.
Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
Front Oncol. 2023 Mar 14;13:1122229. doi: 10.3389/fonc.2023.1122229. eCollection 2023.
Interactions among genetic variants are rarely studied but may explain a part of the variability in patient outcomes.
In this study, we aimed to identify 1 to 3 way interactions among SNPs from five Wnt protein interaction networks that predict the 5-year recurrence risk in a cohort of stage I-III colorectal cancer patients.
423 patients recruited to the Newfoundland Familial Colorectal Cancer Registry were included. Five Wnt family member proteins (Wnt1, Wnt2, Wnt5a, Wnt5b, and Wnt11) were selected. The BioGRID database was used to identify the proteins interacting with each of these proteins. Genotypes of the SNPs located in the interaction network genes were retrieved from a genome-wide SNP genotype data previously obtained in the patient cohort. The GMDR 0.9 program was utilized to examine 1-, 2-, and 3-SNP interactions using a 5-fold cross validation step. Top GMDR 0.9 models were assessed by permutation testing and, if significant, prognostic associations were verified by multivariable logistic regression models.
GMDR 0.9 has identified novel 1, 2, and 3-way SNP interactions associated with 5-year recurrence risk in colorectal cancer. Nine of these interactions were multi loci interactions (2-way or 3-way). Identified interaction models were able to distinguish patients based on their 5-year recurrence-free status in multivariable regression models. The significance of interactions was the highest in the 3-SNP models. Several of the identified SNPs were eQTLs, indicating potential biological roles of the genes they were associated with in colorectal cancer recurrence.
We identified novel interacting genetic variants that associate with 5-year recurrence risk in colorectal cancer. A significant portion of the genes identified were previously linked to colorectal cancer pathogenesis or progression. These variants and genes are of interest for future functional and prognostic studies. Our results provide further evidence for the utility of GMDR models in identifying novel prognostic biomarkers and the biological importance of the Wnt pathways in colorectal cancer.
基因变异之间的相互作用鲜有研究，但可能解释患者预后变异性的一部分。
在本研究中，我们旨在识别来自五个Wnt蛋白相互作用网络的单核苷酸多态性（SNP）之间的一至三种相互作用方式，这些相互作用可预测I - III期结直肠癌患者队列中的5年复发风险。
纳入招募到纽芬兰家族性结直肠癌登记处的423例患者。选择了五种Wnt家族成员蛋白（Wnt1、Wnt2、Wnt5a、Wnt5b和Wnt11）。使用BioGRID数据库识别与这些蛋白中的每一种相互作用的蛋白。位于相互作用网络基因中的SNP的基因型从先前在患者队列中获得的全基因组SNP基因型数据中检索。利用GMDR 0.9程序通过5折交叉验证步骤检查单、双和三SNP相互作用。通过置换检验评估顶级GMDR 0.9模型，若具有显著性，则通过多变量逻辑回归模型验证预后关联。
GMDR 0.9已识别出与结直肠癌5年复发风险相关的新型单、双和三SNP相互作用。其中九种相互作用为多位点相互作用（双位点或三位点）。在多变量回归模型中，所识别的相互作用模型能够根据患者的5年无复发生存状态进行区分。三位点SNP模型中相互作用的显著性最高。所识别的几个SNP是表达数量性状基因座（eQTL），表明它们所关联的基因在结直肠癌复发中具有潜在生物学作用。
我们识别出了与结直肠癌5年复发风险相关的新型相互作用基因变异。所识别的基因中有很大一部分先前与结直肠癌的发病机制或进展相关。这些变异和基因对于未来的功能和预后研究具有重要意义。我们的结果为GMDR模型在识别新型预后生物标志物方面的实用性以及Wnt通路在结直肠癌中的生物学重要性提供了进一步证据。
