Genone-wide Discovery of Molecular Alterations in Head and Neck Cancer

头颈癌分子改变的全基因组发现

• 批准号: 7938027
• 负责人: Nishant Agrawal
• 金额: $ 125.26万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938027
• 关键词: Affect; Appearance; Arts; Bioinformatics; Breast; Cessation of life; Clinical; Code; Colon; Colon Carcinoma; Common Neoplasm; Communities; Computer software; Coupled; DNA; DNA Sequence; DNA Sequence Analysis; Data; Deglutition; Development; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Economics; Employment; Exons; Gastrointestinal tract structure; Gene Expression; Gene Expression Alteration; Gene Expression Microarray Analysis; Gene Mutation; General Population; Genes; Genomics; Glioblastoma; Grant; Head and Neck Cancer; Head and neck structure; Human; Human Genome; Individual; Intervention; Lung; Malignant Neoplasms; Malignant neoplasm of pancreas; Methylation; Modeling; Molecular; Morbidity - disease rate; Mouth Neoplasms; Mutate; Mutation; Nucleotides; Oropharyngeal; Pancreas; Pathway interactions; Patients; Phonation; Prevalence; Proteins; Research; Sampling; Screening procedure; Sequence Analysis; Signal Pathway; Speech; Staging; Taste Perception; Therapeutic; United States; Variant; anticancer research; base; cancer type; cost; density; experience; genome-wide; malignant mouth neoplasm; mortality; mouth squamous cell carcinoma; next generation; novel; novel therapeutics; prognostic; promoter; public health relevance; serial analysis of gene expression; sound; tumor; tumorigenesis

DESCRIPTION (provided by applicant): For this ARRA RFA-OD-09-004 GO application, we propose to perform an integrated genome-wide mutational analysis of oral cancers using high throughput sequence analysis of coding genes combined with analyses of copy number, gene expression, and methylation. Genetic alterations represent the underlying cause of human cancer, including tumors of the oral cavity. In the United States, oral cancers represent ~50% of the 46,000 cases of head and neck cancers. Oral cancer affects physical appearance and vital functions, including taste, swallowing, and speech/phonation. In addition to significant morbidity, head and neck cancer result in ~12,000 deaths, of which oral cancer will be responsible for ~5,400 deaths. Given the significant morbidity and mortality of these tumors, there is a profound need for novel clinical approaches for oral cancer. This project will identify potential new avenues for therapeutic, diagnostic and prognostic intervention in oral cancer, and will serve as a model for genomic analyses of other head and neck cancers. For mutational screening, we will employ the two stage, high throughput DNA sequencing approach that we have recently refined and used to identify novel tumor-relevant mutations in breast, colon, pancreatic, and glioblastoma tumors. This strategy significantly increases the power and reduces the cost of large scale tumor sequencing, providing highly sensitive mutational analysis of >95% of bases of ~200,000 exons from over 20,000 coding genes. In the first stage of this approach, exon sequencing analysis will be performed on a set of 24 clinically annotated oral cancer samples. All mutations will be examined in a normal DNA sample from the same patient to identify and confirm tumor-specific mutations. In the second stage, the mutated genes will be analyzed by sequencing a larger set of at least 48 tumors. Previously developed biostatistical criteria will be applied to discriminate between tumor-relevant driver and irrelevant passenger mutations. In the same set of oral cancer samples examined for mutations, we will also perform copy number analysis using high density SNP microarrays, gene expression analysis by combination of next generation sequencing and serial analysis of gene expression (SAGE), and gene methylation analysis by Infinium methylation microarrays. Bioinformatics analyses will integrate these findings with mutational data, following a signaling pathways perspective that has proved to be powerful in our recent studies. Our hypothesis, based on experience in other tumor types, is that copy number changes and expression loss by promoter methylation, acting in concert with mutations, will be enriched in pathways that are important for development of oral cancer. As has been the case in other cancer types, identification of these altered signaling pathways is likely to provide potential therapeutic strategies for oral cancer. This grant is expected to have a significant economic effect, resulting in the employment of individuals performing genomic research on oral cancer and in subsequent studies of head and neck cancers in general. PUBLIC HEALTH RELEVANCE: We propose to perform an integrated genome-wide mutational analysis of oral cancers using high throughput sequence analysis of coding genes combined with analyses of copy number, gene expression, and methylation.

描述（由申请人提供）：对于此ARRA RFA-OD-09-004 GO应用程序，我们建议使用对编码基因的高吞吐量序列分析以及拷贝数，基因表达和甲基化的分析进行编码基因的高吞吐量序列分析，对口服癌症进行整合的整体基因组突变分析。遗传改变代表了人类癌症的根本原因，包括口腔肿瘤。在美国，口服癌症占46,000例头颈癌病例中的约50％。口腔癌影响外观和重要功能，包括口味，吞咽和语音/发音。除了明显的发病率外，头颈癌还会导致约12,000例死亡，其中口腔癌将导致约5,400例死亡。鉴于这些肿瘤的发病率和死亡率很大，因此对口腔癌的新型临床方法非常需要。该项目将确定口腔癌治疗，诊断和预后干预的潜在新途径，并将作为其他头颈癌基因组分析的模型。为了进行突变筛选，我们将采用最近精炼的两个阶段，高吞吐量的DNA测序方法，并用于鉴定乳腺，结肠，胰腺和胶质母细胞瘤肿瘤中新型肿瘤相关的突变。该策略可显着提高功率并降低了大规模肿瘤测序的成本，从而对超过20,000个编码基因的基95％的基95％的外显子提供了高度敏感的突变分析。在这种方法的第一阶段，将对一组24个临床注释的口腔癌样品进行外显子测序分析。所有突变将在同一患者的正常DNA样品中检查，以识别和确认肿瘤特异性突变。在第二阶段，将通过对较大的至少48个肿瘤进行测序来分析突变的基因。先前开发的生物统计标准将应用于区分与肿瘤相关的驱动器和无关的乘客突变。在检查突变的同一组口腔癌样品中，我们还将使用高密度SNP微阵列进行拷贝数分析，通过下一代测序的结合和基因表达的序列分析（SAGE）（SAGE）（SAGE）的序列分析，以及通过甲基化微阵列的基因甲基化分析。生物信息学分析将遵循信号传导途径的观点，将这些发现与突变数据相结合，在我们最近的研究中被证明是强大的。我们基于其他肿瘤类型的经验的假设是，启动子甲基化的拷贝数变化和表达丧失与突变作用，将富集在对口腔癌发展至关重要的途径中。与其他癌症类型一样，对这些改变的信号通路的识别可能会为口腔癌提供潜在的治疗策略。预计该赠款将产生重大的经济影响，从而导致对对口腔癌进行基因组研究的个人以及随后对头颈癌的研究。 公共卫生相关性：我们建议使用对拷贝数，基因表达和甲基化分析的编码基因的高吞吐量序列分析对口服癌症进行整体基因组突变分析。