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BRAF mutation-specific promoter methylation of FOX genes in colorectal cancer

机译：大肠癌中FOX基因的BRAF突变特异性启动子甲基化

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BackgroundCancer-specific hypermethylation of (promoter) CpG islands is common during the tumorigenesis of colon cancer. Although associations between certain genetic aberrations, such as BRAF mutation and microsatellite instability, and the CpG island methylator phenotype (CIMP), have been found, the mechanisms by which these associations are established are still unclear. We studied genome-wide DNA methylation differences between colorectal tumors carrying a BRAF mutation and BRAF wildtype tumors. ResultsUsing differential methylation hybridization on oligonucleotide microarrays representing 32,171 CpG-rich regions, we identified 1,770 regions with differential methylation between colorectal tumor and paired normal colon. Next, we compared the tumorormal methylation ratios between different groups of patients. Related to CIMP, we identified 749 differentially methylated regions, of which 86% had a higher tumorormal methylation ratio in the CIMP-positive group. We identified 758 regions with a BRAF mutation-specific methylation change, of which 96% had a higher tumorormal methylation ratio in the BRAF mutant group. Among the genes affected by BRAF mutation-specific methylation changes, we found enrichment of several cancer-related pathways, including the PI3 kinase and Wnt signaling pathways. To focus on genes that are silenced in a tumor-specific rather than a lineage-specific manner, we used information on the epigenetic silencing mark H3K27me3 in embryonic stem (ES) cells. Among the genes showing BRAF mutation-specific promoter methylation but no H3K27me3 mark in ES cells were forkhead box ( FOX ) transcription factors associated with the PI3 kinase pathway, as well as MLH1 and SMO . Repression of FOXD3 gene expression in tumors could be related to its promoter hypermethylation. ConclusionsWe identified new BRAF mutation-specific methylation changes in colorectal cancer. Epigenetic downregulation of these targets may contribute to mutationally active BRAF -driven tumorigenesis, explaining its association with aberrant DNA methylation.
机译：背景（启动子）CpG岛的癌特异性超甲基化在结肠癌的肿瘤发生过程中很常见。尽管已发现某些遗传畸变之间的关联，例如BRAF突变和微卫星不稳定性，以及CpG岛甲基化子表型（CIMP），但建立这些关联的机制仍不清楚。我们研究了携带BRAF突变的大肠肿瘤与BRAF野生型肿瘤之间的全基因组DNA甲基化差异。结果在代表32,171个富含CpG区域的寡核苷酸微阵列上使用差异甲基化杂交，我们确定了1,770个大肠肿瘤与配对正常结肠之间甲基化差异的区域。接下来，我们比较了不同患者组之间的肿瘤/正常甲基化比率。与CIMP相关，我们确定了749个差异甲基化区域，其中CIMP阳性组中86％的肿瘤/正常甲基化比率更高。我们确定了BRAF突变特异性甲基化变化的758个区域，其中BRAF突变组中96％的肿瘤/正常甲基化比率更高。在受BRAF突变特异性甲基化变化影响的基因中，我们发现了一些与癌症相关的途径的丰富，包括PI3激酶和Wnt信号通路。为了关注以肿瘤特异性而非谱系特异性方式沉默的基因，我们使用了有关胚胎干（ES）细胞中表观遗传沉默标记H3K27me 3 的信息。在ES细胞中显示BRAF突变特异性启动子甲基化但没有H3K27me 3 标记的基因中，有与PI3激酶途径相关的叉头盒（FOX）转录因子，以及MLH1和SMO。 FOXD3基因在肿瘤中的表达抑制可能与其启动子甲基化有关。结论我们鉴定了大肠癌中新的BRAF突变特异性甲基化变化。这些靶标的表观遗传下调可能有助于突变型BRAF驱动的肿瘤发生，从而解释了其与异常DNA甲基化的关系。

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