Interaction between Microsatellite Instability (MSI) and Tumor DNA Methylation in the Pathogenesis of Colorectal Carcinoma.
Interaction between Microsatellite Instability (MSI) and Tumor DNA Methylation in the Pathogenesis of Colorectal Carcinoma.
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DOI：
10.3390/cancers13194956
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发表时间：
2021-10-01
期刊：
影响因子：
5.2
通讯作者：
Kibriya MG
中科院分区：
文献类型：
--
作者：
Jasmine F;Haq Z;Kamal M;Raza M;da Silva G;Gorospe K;Paul R;Strzempek P;Ahsan H;Kibriya MG
在结直肠癌（CRC）中，突变可能发生在短的重复DNA序列中，称为微卫星不稳定性（MSI）。肿瘤DNA甲基化是另一种分子变化，现在被认为是CRC的重要生物标志物。在全基因组范围内，我们首次探讨了DNA甲基化是否与CRC的MSI状态相关。我们分析了来自125名不同阶段的CRC患者（m = 72，f = 53）的250个配对样本（肿瘤和相应的正常）。我们发现，与正常组织相比，肿瘤组织中的许多基因被甲基化。然而，与没有MSI的患者相比，如果患者也患有MSI，则肿瘤中显示出这种甲基化变化的基因几乎是没有MSI的患者的四倍。我们的研究显示了CRC中MSI和DNA甲基化的相关性。该研究还表明，某些免疫检查点抑制剂（CTLA 4和HAVCR 2抑制剂）可能用于MSI CRC。在结直肠癌（CRC）中，微卫星不稳定性（MSI）的作用是众所周知的。在全基因组范围内，我们首次探讨了差异甲基化是否与MSI相关。我们分析了来自125例CRC患者（m = 72，f = 53）在不同阶段的250个配对样本。其中101例为左侧结直肠癌，30例为MSI，34例为KRAS原癌基因（KRAS）体细胞突变，6例为B-Raf原癌基因（BRAF）外显子15p.V600E突变。MSI在右侧肿瘤中更常见（54% vs. 17%，p = 0.003）。在微卫星稳定（MSS）CRC中，配对比较显示1641个差异甲基化位点（DML），覆盖FDR 0.001的686个基因，Δ β ≥ 20%。在MSI中进行类似的分析，发现6209个DML覆盖2316个基因。包括相互作用（肿瘤 *MSI）的ANOVA模型显示23，322个位点，其中MSI和MSS患者之间的δ β不同。我们的研究表明在CRC的发病机制中MSI和肿瘤DNA甲基化之间存在关联。鉴于本研究中观察到的相互作用，在寻找CRC中的甲基化标记物时，可能值得考虑MSI状态。该研究还表明，某些免疫检查点抑制剂（CTLA 4和HAVCR 2抑制剂）可能用于MSI CRC。
In colorectal cancer (CRC), mutations may occur in short, repeated DNA sequences, known as microsatellite instability (MSI). Tumor DNA methylation is another molecular change now recognized as an important biomarker in CRC. In a genome-wide scale, for the first time, we explored whether DNA methylation is associated with MSI status in CRC. We analyzed 250 paired samples (tumor and corresponding normal) from 125 CRC patients (m = 72, f = 53) at different stages. We found that many genes were methylated in tumor tissue compared to normal tissue. However, almost four times more genes showed such methylation changes in the tumor if the patient who also had MSI compared to patients without MSI. Our study shows an association of MSI and DNA methylation in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI. In colorectal cancer (CRC), the role of microsatellite instability (MSI) is well known. In a genome-wide scale, for the first time, we explored whether differential methylation is associated with MSI. We analyzed 250 paired samples from 125 CRC patients (m = 72, f = 53) at different stages. Of them, 101 had left-sided CRC, 30 had MSI, 34 had somatic mutation in KRAS proto-oncogene (KRAS), and 6 had B-Raf proto-oncogene (BRAF) exon 15p.V600E mutation. MSI was more frequent in right-sided tumors (54% vs. 17%, p = 0.003). Among the microsatellite stable (MSS) CRC, a paired comparison revealed 1641 differentially methylated loci (DML) covering 686 genes at FDR 0.001 with delta beta ≥ 20%. Similar analysis in MSI revealed 6209 DML covering 2316 genes. ANOVA model including interaction (Tumor*MSI) revealed 23,322 loci, where the delta beta was different among MSI and MSS patients. Our study shows an association between MSI and tumor DNA methylation in the pathogenesis of CRC. Given the interaction seen in this study, it may be worth considering the MSI status while looking for methylation markers in CRC. The study also indicates an opportunity for potential use of certain immune checkpoint inhibitors (CTLA4 and HAVCR2 inhibitors) in CRC with MSI.
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