Epigenetic Aging Signatures Are Coherently Modified in Cancer.
Epigenetic Aging Signatures Are Coherently Modified in Cancer.
复制标题
表观遗传性衰老特征在癌症中连贯地改变了。
DOI：
10.1371/journal.pgen.1005334
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发表时间：
2015-06
期刊：
影响因子：
4.5
通讯作者：
Wagner W
中科院分区：
文献类型：
--
作者：
Lin Q;Wagner W
衰老与高度可重复的DNA甲基化（DNAm）变化有关，这可能导致老年人恶性疾病的更高患病率。在这项研究中，我们分析了来自癌症基因组图谱（TCGA）的25种癌症类型的5,621个DNAm谱的表观遗传衰老特征。总的来说，与年龄相关的dna模式几乎不能反映癌症患者的实际年龄，但它们以非随机方式连贯地改变，特别是在非恶性组织中随着年龄的增长而变得高甲基化的CpGs。因此，这种表观遗传衰老特征的协调调节可用于异常的表观遗传年龄预测，从而促进疾病分层。例如，在急性髓性白血病（AML）中，较高的表观遗传年龄预测与RUNX1、WT1和IDH2突变的发生率增加有关，而TET2、TP53和PML-PARA易位突变在较年轻的年龄预测中更为常见。此外，表观遗传衰老特征与几种类型癌症（如低级别胶质瘤、多形性胶质母细胞瘤、食管癌、憎色性肾细胞癌、皮肤黑色素瘤、肺鳞状细胞癌和神经内分泌肿瘤）的总生存率相关。总之，癌症中与年龄相关的dna模式与患者的实足年龄无关，但它们是协调调节的，特别是在正常衰老中变得高甲基化的CpGs中。此外，表观遗传年龄预测与几种癌症的临床参数和总生存率相关，表明年龄相关CpGs中dna模式的调节与癌症发展有关。我们的基因组包含表观遗传标记，如胞嘧啶残基上的DNA甲基化（DNAm），它控制着细胞分化。一些表观遗传修饰以一种高度可复制的方式在一生中积累——它们可能有助于衰老过程，并促进可靠的年龄预测。到目前为止，我们还不知道这些“表观遗传衰老特征”是如何在癌症组织中被改变的，以及与正常组织相比，它们是否会加速。在这项研究中，我们系统地分析了许多类型癌症中与年龄相关的dna模式。与非恶性组织相比，表观遗传老化特征几乎不能反映癌症患者的实际年龄。这可能至少部分归因于这样一个事实，即癌症是一种克隆疾病，只捕获肿瘤起始细胞的表观遗传组成。值得注意的是，异常的dna模式不是随机分布的，而是在非恶性组织中随着年龄的增长而甲基化的区域中显示了共同调控。此外，我们证明了表观遗传年龄预测的偏差与临床参数相关。事实上，它们与许多类型癌症的总体生存率明显相关。这些发现尤其重要，因为它们表明了年龄相关的DNA甲基化模式与恶性转化、癌症发展和预后的相关性。
Aging is associated with highly reproducible DNA methylation (DNAm) changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA). Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a non-stochastic manner, particularly at CpGs that become hypermethylated upon aging in non-malignant tissues. This coordinated regulation in epigenetic aging signatures can therefore be used for aberrant epigenetic age-predictions, which facilitate disease stratification. For example, in acute myeloid leukemia (AML) higher epigenetic age-predictions are associated with increased incidence of mutations in RUNX1, WT1, and IDH2, whereas mutations in TET2, TP53, and PML-PARA translocation are more frequent in younger age-predictions. Furthermore, epigenetic aging signatures correlate with overall survival in several types of cancer (such as lower grade glioma, glioblastoma multiforme, esophageal carcinoma, chromophobe renal cell carcinoma, cutaneous melanoma, lung squamous cell carcinoma, and neuroendocrine neoplasms). In conclusion, age-associated DNAm patterns in cancer are not related to chronological age of the patient, but they are coordinately regulated, particularly at CpGs that become hypermethylated in normal aging. Furthermore, the apparent epigenetic age-predictions correlate with clinical parameters and overall survival in several types of cancer, indicating that regulation of DNAm patterns in age-associated CpGs is relevant for cancer development. Our genome harbors epigenetic marks, such as DNA methylation (DNAm) at cytosine residues, which govern cellular differentiation. Some epigenetic modifications accumulate throughout life in a highly reproducible manner–they may contribute to the aging process and facilitate reliable age-predictions. So far, little is known how these “epigenetic aging signatures” are modified in cancer tissue and whether or not they are accelerated as compared to normal tissue. In this study, we systematically analyzed age-associated DNAm patterns in many types of cancer. In contrast to non-malignant tissue the epigenetic aging signatures hardly reflect chronological age of cancer patients. This may at least partially be attributed to the fact that cancer is a clonal disease capturing only the epigenetic make-up of the tumor-initiating cell. Notably, the aberrant DNAm patterns are not randomly distributed but reveal co-regulation at regions that become methylated upon aging in non-malignant tissue. Furthermore, we demonstrate that deviations of epigenetic age-predictions correlate with clinical parameters. In fact, they are clearly associated with overall survival in many types of cancer. These findings are particularly important, as they indicate relevance of age-associated DNA methylation patterns for malignant transformation, cancer development and prognosis.
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影响因子：
4.5
作者：
Grönniger E;Weber B;Heil O;Peters N;Stäb F;Wenck H;Korn B;Winnefeld M;Lyko F
通讯作者：
Lyko F
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：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
3.7
作者：
Bocklandt S;Lin W;Sehl ME;Sánchez FJ;Sinsheimer JS;Horvath S;Vilain E
通讯作者：
Vilain E