Integrative epigenetic and genetic pan-cancer somatic alteration portraits.
Integrative epigenetic and genetic pan-cancer somatic alteration portraits.
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DOI：
10.1080/15592294.2017.1319043
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发表时间：
2017-07-03
期刊：
影响因子：
3.7
通讯作者：
Christensen BC
中科院分区：
文献类型：
--
作者：
Salas LA;Johnson KC;Koestler DC;O'Sullivan DE;Christensen BC
遗传和表观遗传改变是致癌所必需的，并且已经研究了肿瘤类型之间的突变负荷。在这里，我们研究了表观遗传学改变与全球DNA甲基化失调的新措施，甲基化失调指数（MDI），在癌症基因组图谱（TCGA）数据库中的14种癌症类型。从TCGA获得DNA甲基化数据-使用Illumina HumanMethylation 450 BeadChip获得。我们计算了14种肿瘤类型（n = 5，592个肿瘤）的MDI，使用每个肿瘤部位的相邻正常组织（n = 701）。从cBioportal（n = 5，152）检索拷贝数改变和突变负荷。我们测试了受试者MDI在肿瘤中的关系，以及与年龄、性别、肿瘤分期、估计的肿瘤纯度和总体MDI和基因组背景特异性MDI的拷贝数变化的关系。我们还研究了肿瘤类型中最常见的失调基因座。在肿瘤类型中存在广泛的甲基化失调程度（P < 2.2E-16）。然而，在肿瘤类型中观察到了按基因组背景分层的一致的甲基化失调模式，其中最高的失调发生在非CpG岛区域。考虑到体细胞改变的其他概括性措施，MDI与拷贝数改变相关，但与突变负荷无关。使用肿瘤中常见的最高失调CpG位点，观察到4类癌症类型，并证实了这些基因表达改变的功能后果。这项工作确定了14种癌症类型的整体DNA甲基化失调模式，显示出对非CpG岛区域的影响更大。癌症类型中最失调的基因座确定了癌症类型中可能对未来治疗和预防措施产生影响的共同集群。
Genetic and epigenetic alterations are required for carcinogenesis and the mutation burden across tumor types has been investigated. Here, we investigate epigenetic alterations with a novel measure of global DNA methylation dysregulation, the methylation dysregulation index (MDI), across 14 cancer types in The Cancer Genome Atlas (TCGA) database. DNA methylation data—obtained using Illumina HumanMethylation450 BeadChip—was accessed from TCGA. We calculated the MDI in 14 tumor types (n = 5,592 tumors), using adjacent normal tissues (n = 701) from each tumor site. Copy number alteration, and mutation burden were retrieved from cBioportal (n = 5,152). We tested the relation of subject MDI across tumors and with age, gender, tumor stage, estimated tumor purity, and copy number alterations for both overall MDI and genomic-context-specific MDI. We also investigated the top most dysregulated loci shared across tumor types. There was a broad range of extent in methylation dysregulation across tumor types (P < 2.2E-16). However, a consistent pattern of methylation dysregulation stratified by genomic context was observed across tumor types where the highest dysregulation occurred at non-CpG island regions. Considering other summary measures of somatic alteration, MDI was correlated with copy number alterations but not with mutation burden. Using the top dysregulated CpG sites in common across tumors, 4 classes of cancer types were observed, and the functional consequences of these alterations to gene expression were confirmed. This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas. The most dysregulated loci across cancer types identified common clusters across cancer types that may have implications for future treatment and prevention measures.
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影响因子：
4.5
作者：
Christensen BC;Houseman EA;Marsit CJ;Zheng S;Wrensch MR;Wiemels JL;Nelson HH;Karagas MR;Padbury JF;Bueno R;Sugarbaker DJ;Yeh RF;Wiencke JK;Kelsey KT
通讯作者：
Kelsey KT
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network