Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis.
Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis.
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DOI：
10.1371/journal.pmed.0050114
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发表时间：
2008-05-27
期刊：
影响因子：
15.8
通讯作者：
Baylin, Stephen B.
中科院分区：
文献类型：
--
作者：
Chan, Timothy A.;Glockner, Sabine;Yi, Joo Mi;Chen, Wei;Van Neste, Leander;Cope, Leslie;Herman, James G.;Velculescu, Victor;Schuebel, Kornel E.;Ahuja, Nita;Baylin, Stephen B.
肿瘤抑制基因的鉴定和表征增强了我们对癌症生物学的理解，并使新的诊断和治疗方式的发展成为可能。然而在过去的几十年里，使用连锁分析等技术已经缓慢地鉴定出少数肿瘤抑制因子，而大规模的癌症基因组测序使得快速鉴定出大量在癌症中突变的基因成为可能。然而，确定这些基因中哪些在癌症发展中起关键作用已被证明是具有挑战性的。具体来说，最近对人类乳腺癌和结肠癌的测序揭示了大量的体细胞基因突变，但几乎所有突变都是杂合的，发生频率低，并且是肿瘤类型特异性的。我们假设癌症中的关键抑癌基因可能会发生突变或超甲基化。在这里，我们展示了这些基因的综合遗传和表观遗传分析揭示了许多具有更高的推定肿瘤抑制状态。在新近发现的189个突变基因中，至少有36个是启动子CpG岛超甲基化的靶点，通常存在于结肠癌和乳腺癌细胞系中。对原发肿瘤的分析表明，这些基因中的18个在原发癌症中被高度甲基化，其发生率往往远高于突变，而且并不局限于单一的肿瘤类型。在鉴定出突变的相同乳腺癌细胞系中，高甲基化通常（但并非总是）与特定肿瘤的遗传变化相互排斥，并且伴随表达缺失的发生率很高。这18个基因中有16个（89%）与人类癌症中缺失的基因位点相对应。最后，也是最重要的是，这些基因子集的表达减少与不良的临床结果密切相关。使用无偏见的全基因组方法，我们的分析已经发现了乳腺癌和结肠癌中多种失活模式的一些临床重要基因。重要的是，我们证明了这些基因的一个子集强烈预测了不良的临床结果。我们的数据定义了一组基因，这些基因是遗传和表观遗传事件的目标，预测临床预后，并且可能对癌症的发生或进展至关重要。Stephen Baylin和他的同事们通过对乳腺癌和结肠癌的综合遗传和表观遗传分析，发现了许多具有临床意义的基因，这些基因被多种失活模式所靶向。癌症是发达国家最大的杀手之一，例如，每年有超过50万的美国人死于癌症。因此，人们对了解癌症的遗传和环境原因非常感兴趣，以改善癌症的预防、诊断和治疗。当细胞开始繁殖失控时，癌症就开始了。DNA是编码指令的序列——基因——用于构造和维持身体。例如，某些“肿瘤抑制”基因通过阻止肿瘤的发展来帮助预防癌症，但是改变DNA密码序列的变化——突变——可以深刻地影响基因的工作方式。现代遗传分析技术已经确定了诸如肿瘤抑制因子等基因，当这些基因发生突变时，与某些癌症的发展有关。然而，近年来，越来越明显的是，突变既不是解释所有癌症病例的必要条件，也不是充分条件。这使得研究人员开始关注所谓的表观遗传因素，它也会在不改变DNA序列的情况下改变基因的工作方式。这方面的一个例子是“甲基化”，它通过化学标签阻止基因表达——使其失活。基因甲基化是DNA正常功能的一部分，但异常甲基化与癌症、衰老和一些罕见的出生异常有关。先前对乳腺癌和结肠癌细胞DNA的分析揭示了189个“候选癌症基因”——与乳腺癌和结肠癌的发展有关的突变基因。然而，目前还不清楚这些突变是如何导致癌症的，个别突变只出现在5%到15%的特定肿瘤中。这项研究的作者想知道甲基化等表观遗传因素是否会导致癌症。研究人员首先确定了189个候选癌症基因中的56个可能是肿瘤抑制基因，然后确定其中36个基因被甲基化和失活，通常在乳腺癌和结肠癌（实验室生长的）癌细胞中。在几乎所有的情况下，甲基化的基因都不活跃，但可以通过去甲基化来重新激活。他们进一步表明，在正常的结肠和乳房组织样本中，36个基因中有18个未甲基化，功能正常，但在取自乳腺癌和结肠癌肿瘤的细胞中，它们被甲基化了。与基因突变相反，这18个基因在一系列肿瘤类型中经常甲基化，其中8个基因在乳腺癌和结肠癌中都甲基化。作者通过回顾乳腺癌和结肠癌中这18个基因的遗传学和表观遗传学发现，它们要么突变，要么甲基化，要么两者兼而有之。一项文献综述显示，已知18个基因中至少有6个具有肿瘤抑制特性，作者确定其中16个位于已知从一系列癌症肿瘤细胞中缺失的DNA部分。最后，研究人员分析了癌症病例的数据，表明这18个基因的甲基化与这些基因在肿瘤中的功能降低有关，并且癌症晚期或扩散到身体其他部位的可能性更大。研究人员只考虑了在之前的一项研究中发现的189个候选癌症基因，而没有考虑其他地方发现的其他基因。他们也没有考虑在这些基因中发现的个体突变的生物学效应。尽管如此，他们已经证明，特定基因的甲基化可能在乳腺癌和/或结肠癌细胞的发展中发挥作用，要么与突变一起发挥作用，要么独立发挥作用，最有可能的是关闭它们的肿瘤抑制功能。然而，更广泛地说，这项研究进一步证明，未来对基因在癌症中的作用的分析应该包括表观遗传因素和遗传因素。此外，作者还表明，其中一些基因可能对预测一系列肿瘤类型的临床结果有用。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0050114访问这些网站。2006年12月的一篇《公共科学图书馆医学展望》文章回顾了甲基化作为常见癌症因素的研究价值及其在早期检测中的应用。美国癌症协会的网站上有大量关于各种癌症的信息和资源，包括乳腺癌和结肠癌。约翰霍普金斯大学的Sidney Kimmel综合癌症中心发布了作者关于甲基化研究的背景信息，阐述了甲基化在早期诊断和更好治疗癌症方面的潜力
The identification and characterization of tumor suppressor genes has enhanced our understanding of the biology of cancer and enabled the development of new diagnostic and therapeutic modalities. Whereas in past decades, a handful of tumor suppressors have been slowly identified using techniques such as linkage analysis, large-scale sequencing of the cancer genome has enabled the rapid identification of a large number of genes that are mutated in cancer. However, determining which of these many genes play key roles in cancer development has proven challenging. Specifically, recent sequencing of human breast and colon cancers has revealed a large number of somatic gene mutations, but virtually all are heterozygous, occur at low frequency, and are tumor-type specific. We hypothesize that key tumor suppressor genes in cancer may be subject to mutation or hypermethylation. Here, we show that combined genetic and epigenetic analysis of these genes reveals many with a higher putative tumor suppressor status than would otherwise be appreciated. At least 36 of the 189 genes newly recognized to be mutated are targets of promoter CpG island hypermethylation, often in both colon and breast cancer cell lines. Analyses of primary tumors show that 18 of these genes are hypermethylated strictly in primary cancers and often with an incidence that is much higher than for the mutations and which is not restricted to a single tumor-type. In the identical breast cancer cell lines in which the mutations were identified, hypermethylation is usually, but not always, mutually exclusive from genetic changes for a given tumor, and there is a high incidence of concomitant loss of expression. Sixteen out of 18 (89%) of these genes map to loci deleted in human cancers. Lastly, and most importantly, the reduced expression of a subset of these genes strongly correlates with poor clinical outcome. Using an unbiased genome-wide approach, our analysis has enabled the discovery of a number of clinically significant genes targeted by multiple modes of inactivation in breast and colon cancer. Importantly, we demonstrate that a subset of these genes predict strongly for poor clinical outcome. Our data define a set of genes that are targeted by both genetic and epigenetic events, predict for clinical prognosis, and are likely fundamentally important for cancer initiation or progression. Stephen Baylin and colleagues show that a combined genetic and epigenetic analysis of breast and colon cancers identifies a number of clinically significant genes targeted by multiple modes of inactivation. Cancer is one of the developed world's biggest killers—over half a million Americans die of cancer each year, for instance. As a result, there is great interest in understanding the genetic and environmental causes of cancer in order to improve cancer prevention, diagnosis, and treatment. Cancer begins when cells begin to multiply out of control. DNA is the sequence of coded instructions—genes—for how to build and maintain the body. Certain “tumor suppressor” genes, for instance, help to prevent cancer by preventing tumors from developing, but changes that alter the DNA code sequence—mutations—can profoundly affect how a gene works. Modern techniques of genetic analysis have identified genes such as tumor suppressors that, when mutated, are linked to the development of certain cancers. However, in recent years, it has become increasingly apparent that mutations are neither necessary nor sufficient to explain every case of cancer. This has led researchers to look at so-called epigenetic factors, which also alter how a gene works without altering its DNA sequence. An example of this is “methylation,” which prevents a gene from being expressed—deactivates it—by a chemical tag. Methylation of genes is part of the normal functioning of DNA, but abnormal methylation has been linked with cancer, aging, and some rare birth abnormalities. Previous analysis of DNA from breast and colon cancer cells had revealed 189 “candidate cancer genes”—mutated genes that were linked to the development of breast and colon cancer. However, it was not clear how those mutations gave rise to cancer, and individual mutations were present in only 5% to 15% of specific tumors. The authors of this study wanted to know whether epigenetic factors such as methylation contributed to causing the cancers. The researchers first identified 56 of the 189 candidate cancer genes as likely tumor suppressors and then determined that 36 of these genes were methylated and deactivated, often in both breast and colon (laboratory-grown) cancer cells. In nearly all cases, the methylated genes were not active but could be reactivated by being demethylated. They further showed that, in normal colon and breast tissue samples, 18 of the 36 genes were unmethylated and functioned normally, but in cells taken from breast and colon cancer tumors they were methylated. In contrast to the genetic mutations, the 18 genes were frequently methylated across a range of tumor types, and eight genes were methylated in both the breast and colon cancers. The authors found by reviewing the genetics and epigenetics of those 18 genes in breast and colon cancer that they were either mutated, methylated, or both. A literature review showed that at least six of the 18 genes were known to have tumor suppressor properties, and the authors determined that 16 were located in parts of DNA known to be missing from cells taken from a range of cancer tumors. Finally, the researchers analyzed data on cancer cases to show that methylation of these 18 genes was correlated with reduced function of these genes in tumors and with a greater likelihood that a cancer will be terminal or spread to other parts of the body. The researchers considered only the 189 candidate cancer genes found in one previous study and not other genes identified elsewhere. They also did not consider the biological effects of the individual mutations found in those genes. Despite this, they have demonstrated that methylation of specific genes is likely to play a role in the development of breast and/or colon cancer cells either together with mutations or independently, most likely by turning off their tumor suppression function. More broadly, however, the study adds to the evidence that future analysis of the role of genes in cancer should include epigenetic as well as genetic factors. In addition, the authors have also shown that a number of these genes may be useful for predicting clinical outcomes for a range of tumor types. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050114. A December 2006 PLoS Medicine Perspective article reviews the value of examining methylation as a factor in common cancers and its use for early detection The Web site of the American Cancer Society has a wealth of information and resources on a variety of cancers, including breast and colon cancer Breastcancer.org is a nonprofit organization providing information about breast cancer on the Web, including research news Cancer Research UK provides information on cancer research The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins publishes background information on the authors' research on methylation, setting out its potential for earlier diagnosis and better treatment of cancer
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
8.8
作者：
Bouffler SD;Hofland N;Cox R;Fodde R
通讯作者：
Fodde R
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
8
作者：
Alberici, P;Jagmohan-Changur, S;Fodde, R
通讯作者：
Fodde, R