Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
PLoS One. 2018 Apr 25;13(4):e0196233. doi: 10.1371/journal.pone.0196233. eCollection 2018.
Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non-synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted.
一碳代谢、核苷酸合成和甲基化相关的细胞内反应的紊乱可能会增加结直肠癌（CRC）的风险。然而，结果并不一致。为了探究这种不一致是否可以归因于肿瘤间异质性，我们评估了一碳代谢生物标志物的综合面板以及一些与 KRAS 和 BRAF 致癌基因突变相关的 CRC 分子亚型风险相关的单核苷酸多态性（SNP）。这项巢式病例对照研究纳入了来自于瑞典北部健康与疾病研究中的两个基于人群的队列的 488 例 CRC 病例和 947 例匹配对照。我们分析了预测性血液中的 14 种生物标志物和 17 个 SNP，并确定了肿瘤组织中的 KRAS 和 BRAF 突变状态。在多变量网络分析中，没有变量与特定 CRC 亚型的风险显示出强烈的关联。CTH 基因中的非同义 SNP，rs1021737，与其他变量相比具有更强的相关性。在随后的单变量分析中，具有变异 rs1021737 基因型的参与者发生 KRAS 突变型 CRC 的风险降低（每个等位基因的比值比=0.72，95%CI=0.50，1.05），而发生 BRAF 突变型 CRC 的风险增加（每个等位基因的比值比=1.56，95%CI=1.07，2.30），异质性的证据较弱（Pheterogeneity=0.01）。在来自癌症基因组图谱的 533 例 CRC 病例的病例-病例分析中，没有发现这种亚型特异性 SNP 关联（P=0.85）。总之，我们没有发现一碳代谢生物标志物和 SNP 在 CRC 发展中具有明确的亚型特异性作用的证据，因此先前研究中一碳代谢在 CRC 发展中的作用的不同结果不太可能归因于 CRC 分子亚型分布的差异。需要进一步研究 CTH 基因在结直肠癌发生中与 KRAS 和 BRAF 突变或肿瘤的其他分子特征的关系。
