DNA methylation intratumor heterogeneity in localized lung adenocarcinomas.
DNA methylation intratumor heterogeneity in localized lung adenocarcinomas.
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DOI：
10.18632/oncotarget.15777
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发表时间：
2017-03-28
期刊：
影响因子：
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通讯作者：
Zhang J
中科院分区：
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作者：
Quek K;Li J;Estecio M;Zhang J;Fujimoto J;Roarty E;Little L;Chow CW;Song X;Behrens C;Chen T;William WN;Swisher S;Heymach J;Wistuba I;Zhang J;Futreal A;Zhang J
肿瘤是由特定肿瘤内具有不同分子和表型特征的细胞组成的，这种现象被称为肿瘤内异质性(ITH)。以前，我们已经证明了基因组ITH在局限性肺腺癌中的作用；然而，在肺癌中ITH甲基化的性质还没有得到很好的研究。在这项研究中，我们使用Illumina Infinium人类甲基化450K珠芯片阵列生成了来自11个局限性肺腺癌及其匹配的正常肺组织的48个空间分离的肿瘤区域的甲基化图谱。我们在相同的肿瘤中观察到甲基化ITH，但与个体间的异质性相比，程度要小得多。平均而言，与匹配的正常肺组织相比，来自同一肿瘤的所有区域共享所有差异甲基化探针的25%。这与体细胞突变形成对比，体细胞突变中约77%是个体肿瘤所有区域共同发生的事件，这表明虽然大多数体细胞突变是早期克隆事件，但肿瘤特异性DNA甲基化可能与这11种肿瘤的后期分支进化有关。此外，我们的数据显示，DNA甲基化程度较高与较大的肿瘤大小(平均欧氏距离35.64vs27.24(中位数)，p=0.014)、高龄(平均欧氏距离34.95vs28.06(65以下)，p=0.046)和术后复发风险增加(平均欧氏距离35.65vs29.03(未复发患者)，p=0.039)。
Cancers are composed of cells with distinct molecular and phenotypic features within a given tumor, a phenomenon termed intratumor heterogeneity (ITH). Previously, we have demonstrated genomic ITH in localized lung adenocarcinomas; however, the nature of methylation ITH in lung cancers has not been well investigated. In this study, we generated methylation profiles of 48 spatially separated tumor regions from 11 localized lung adenocarcinomas and their matched normal lung tissues using Illumina Infinium Human Methylation 450K BeadChip array. We observed methylation ITH within the same tumors, but to a much less extent compared to inter-individual heterogeneity. On average, 25% of all differentially methylated probes compared to matched normal lung tissues were shared by all regions from the same tumors. This is in contrast to somatic mutations, of which approximately 77% were shared events amongst all regions of individual tumors, suggesting that while the majority of somatic mutations were early clonal events, the tumor-specific DNA methylation might be associated with later branched evolution of these 11 tumors. Furthermore, our data showed that a higher extent of DNA methylation ITH was associated with larger tumor size (average Euclidean distance of 35.64 (> 3cm, median size) versus 27.24 (<= 3cm), p = 0.014), advanced age (average Euclidean distance of 34.95 (above 65) verse 28.06 (below 65), p = 0.046) and increased risk of postsurgical recurrence (average Euclidean distance of 35.65 (relapsed patients) versus 29.03 (patients without relapsed), p = 0.039).