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）：对于该 ARRA RFA-OD-09-004 GO 申请，我们建议使用编码基因的高通量序列分析结合拷贝数、基因表达和甲基化分析，对口腔癌进行集成的全基因组突变分析。基因改变是人类癌症（包括口腔肿瘤）的根本原因。在美国，口腔癌约占 46,000 例头颈癌病例的 50%。口腔癌影响身体外观和重要功能，包括味觉、吞咽和言语/发声。除了显着的发病率外，头颈癌还导致约 12,000 人死亡，其中口腔癌将导致约 5,400 人死亡。鉴于这些肿瘤的显着发病率和死亡率，迫切需要针对口腔癌的新临床方法。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。对于突变筛选，我们将采用我们最近改进的两阶段高通量 DNA 测序方法，该方法用于识别乳腺癌、结肠癌、胰腺癌和胶质母细胞瘤中新的肿瘤相关突变。该策略显着提高了大规模肿瘤测序的能力并降低了成本，对来自超过 20,000 个编码基因的约 200,000 个外显子的 95% 以上的碱基进行了高度灵敏的突变分析。在该方法的第一阶段，将对一组 24 个临床注释的口腔癌样本进行外显子测序分析。所有突变都将在同一患者的正常 DNA 样本中进行检查，以识别和确认肿瘤特异性突变。在第二阶段，将通过对至少 48 个肿瘤的更大组进行测序来分析突变基因。先前制定的生物统计标准将用于区分与肿瘤相关的驱动突变和不相关的乘客突变。在检查突变的同一组口腔癌样本中，我们还将使用高密度SNP微阵列进行拷贝数分析，结合下一代测序和基因表达序列分析（SAGE）进行基因表达分析，以及使用Infinium甲基化微阵列进行基因甲基化分析。生物信息学分析将遵循信号通路的观点，将这些发现与突变数据整合起来，这在我们最近的研究中已被证明是强大的。基于其他肿瘤类型的经验，我们的假设是，启动子甲基化引起的拷贝数变化和表达缺失，与突变协同作用，将丰富对口腔癌发展重要的途径。与其他癌症类型的情况一样，识别这些改变的信号通路可能为口腔癌提供潜在的治疗策略。这笔赠款预计将产生显着的经济影响，从而雇用从事口腔癌基因组研究以及随后的头颈癌研究的个人。 公共卫生相关性：我们建议利用编码基因的高通量序列分析结合拷贝数、基因表达和甲基化分析，对口腔癌进行综合的全基因组突变分析。