Global DNA methylation profiles of head and neck cancers

描述(申请人提供)：头颈癌是世界范围内的常见病，美国每年确诊的病例超过4万例。五年存活率约为50%，20年来没有改善。该研究项目致力于基于头颈部组织的全球表观遗传状况开发一种新的癌症生物标记物范例。在许多实验室，DNA甲基化检测是癌症早期诊断的一种手段。最近，DNA低甲基化被发现是一种很有前途的癌症晚期和侵袭性阶段的生物标志物，迫切需要分析工具，除了启动子相关的CpG岛的异常甲基组外，还需要全面采样隐藏在DNA重复序列中的异常甲基组。这项赠款申请的重点是验证一种新的基于微阵列的方法，用于表观遗传生物标记物的发现和癌症分类，该方法是对目前使用的其他方法的补充。这种新方法相对简单，具有对大多数DNA重复序列和基因启动子的甲基化状态进行采样的独特能力，从而产生非常大的数据集。我们将使用一组来自头颈部癌症患者的具有统计学意义的肿瘤样本，进行基于微阵列的甲基化分析。此外，我们将利用微阵列产生的甲基化特征信息，使用各种分析方法来识别临床上相关的头颈癌亚型。我们将通过包括可用于相同样本的额外数据集来完善亚型分类算法，包括阵列-CGH和HPV感染状态揭示的等位基因获得和丢失，以及相关患者临床数据。我们将利用这一新信息来满足临床迫切的诊断和预后需求，以改进头颈部癌症的分类，包括早期发育阶段的诊断、侵袭性评估、转移可能性和术后复发风险。

DESCRIPTION (provided by applicant): Head and neck cancer is a common disease worldwide, and more than 40,000 cases are diagnosed annually in the United States. The five-year survival rate is roughly 50% and has not improved over two decades. This research project focuses on the development of a new cancer biomarker paradigm based on the global epigenetic status of head and neck tissues. In many laboratories, DNA methylation is being examined as a means for early diagnosis of cancer. Recently DNA hypomethylation has been found to be a promising biomarker for the more advanced and aggressive stages of cancer, and there is an urgent need for analytical tools that will sample comprehensively the abnormal "methylome" hidden within the vast landscape of DNA repeats, in addition to the abnormal methylome of promoter-associated CpG islands. This grant application focuses on the validation of a novel microarray-based approach for epigenetic biomarker discovery and cancer classification that is complementary to other methods currently in use. The new method is relatively simple and has the unique capability to sample the methylation status of the majority of DNA repeats, as well as gene promoters, generating very large data sets. We will perform microarray-based methylation profiling using a statistically meaningful set of tumor samples from head and neck cancer patients. In addition, we will utilize the microarray-generated methylation profile information to identify clinically relevant subtypes of head and neck cancer, using a variety of analytical approaches. We will refine a subtype classification algorithm by inclusion of additional datasets available for the same samples, including allele gains and loses revealed by array-CGH and HPV infection status, as well as relevant patient clinical data. We will use this new information to address urgent diagnostic and prognostic clinical needs for improved classification of head and neck cancers in relation to diagnosis of early developmental stages, assessment of aggressiveness, likelihood of metastasis, and risk of recurrence after surgery.