背景:叶酸参与多种遗传,表观遗传,和代谢过程,叶酸摄入不足与癌症风险增加有关。
目的:我们根据与结直肠癌(CRC)相关基因的体细胞突变,使用靶向测序检查叶酸摄入是否与CRC风险有差异相关。
方法:两个大型CRC联盟中的参与者,提供有关膳食叶酸,补充叶酸,和总叶酸摄入量包括在内。对来自病例的结直肠肿瘤样本进行测序,以确定105个基因和6个信号通路中存在非沉默突变(IGF2/PI3K,MMR,RTK/RAS,TGF-β,WNT,TP53/ATM)。运行多项逻辑回归模型,将突变/非突变CRC病例与对照进行比较,以计算具有95%置信区间(CI)的多变量调整比值比(OR)。使用逻辑回归在仅病例分析中测试了突变与非突变CRC病例关联的异质性。分别在高突变和非高突变肿瘤中进行分析,因为它们表现出不同的临床行为。
结果:我们纳入了4,339例CRC病例(702例超突变肿瘤,16.2%)和11767个对照。总叶酸摄入量与CRC风险呈负相关(OR=0.93,95CI=0.90-0.96)。在高突变肿瘤中,12个基因(AXIN2,B2M,BCOR,CHD1,DOCK3,FBLN2,MAP3K21,POLD1,RYR1,TET2,UTP20,ZNF521)对突变状态的异质性表现出名义上的统计学意义(P<0.05),但在多次测试校正后,没有一个仍然显著。在这些遗传亚型中,叶酸变量和CRC之间的关联大多是相反的或接近零,除了肿瘤突变的DOCK3(补充叶酸),CHD1(总叶酸),和ZNF521(膳食叶酸)显示正相关。我们在非超突变肿瘤的分析中没有观察到差异关联,或根据信号通路。
结论:根据所研究基因的突变,叶酸摄入与CRC风险没有差异相关。在少数基因中观察到的名义上显着的差异突变效应值得进一步研究。
BACKGROUND: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer.
OBJECTIVE: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing.
METHODS: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors.
RESULTS: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways.
CONCLUSIONS: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation.