Mutator Phenotype in Colon Cancer

结肠癌的突变表型

• 批准号: 9390042
• 负责人: LAWRENCE A LOEB
• 金额: $ 35.53万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-25 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9390042
• 关键词: Affect; Base Pairing; Base Sequence; Cell Fraction; Cells; Classification; Clinical; Clinical Trials Design; Colon Carcinoma; Colorectal Cancer; Colorectal Neoplasms; DNA; DNA Damage; DNA Repair; DNA Sequence; DNA Sequence Alteration; DNA biosynthesis; DNA sequencing; Detection; Disease; Disease Outcome; Drug resistance; Evolution; Exhibits; Frequencies; Genes; Genetic; Genetic Variation; Geographic Locations; Goals; Growth; Heterogeneity; Host Defense; Human; Individual; Invaded; Malignant Neoplasms; Measures; Medicine; Methodology; Methods; Mutation; Neoplasm Metastasis; Patient Selection; Patients; Phenotype; Population; Predictive Value; Primary Neoplasm; Prognostic Marker; Proliferating; Protocols documentation; Recurrence; Resistance; Risk; Role; Source; TNM; Testing; anti-cancer; cancer cell; chemotherapeutic agent; chemotherapy; ds-DNA; fitness; molecular subtypes; mutant; next generation; personalized chemotherapy; prognostic value; public health relevance; repository; subclonal heterogeneity; therapy resistant; tumor; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): Recently, the DNA sequence of human cancers has been investigated extensively and shown to contain more than 100,000 alterations in each cancer cell. These results have provided strong evidence to support our long-held hypothesis that normal mutation rates are insufficient to account for the multiple mutations present in cancer cells and that cancers exhibit a mutator phenotype. We have established a new method for next- generation DNA sequencing that gives us unprecedented accuracy. By sequencing both strands of individual DNA molecules we can detect a single mutation when present among 10 million wild type sequences. We desire to apply this to studying subclonal mutations in colon cancer, i.e. mutations that are present in only a small percent of the malignant cells within the tumor and would not be detected by routine next generation DNA sequencing. These mutations could be responsible for the ability of these cancers to circumvent host cell anti-cancer mechanisms and for the rapid emergence of resistance to chemotherapeutic agents in some cancers. We will carry out the following studies: 1) We will use our new method of double-stranded DNA sequencing to quantify the number of subclonal mutations as a function of the ability of individual cancers to proliferate, invade and metastasize; 2) We will determine if cance cell fitness is altered by specific types of mutations resulting from decreased fidelity of DNA replication or efficiency of DNA repair; and 3) We will use this ultra-accurate methodology to determine whether subclonal DNA mutations can be used as prognostic biomarkers. An understanding of the extent and sources of mutational heterogeneity within tumors may substantially affect our assessment of the disease, and greatly advance the delivery of comprehensive personalized chemotherapy.

 描述(申请人提供)：最近，人们对人类癌症的DNA序列进行了广泛的研究，发现每个癌细胞中包含超过10万个变化。这些结果为我们长期坚持的假设提供了强有力的证据，即正常突变率不足以解释癌细胞中存在的多种突变，癌症表现出突变表型。我们已经建立了一种新的下一代DNA测序方法，它给了我们前所未有的准确性。通过对单个DNA分子的两条链进行测序，我们可以在1000万个野生型序列中检测到单个突变。我们希望将其应用于研究结肠癌的亚克隆突变，即只存在于肿瘤内一小部分恶性细胞中且无法通过常规下一代DNA测序检测到的突变。这些突变可能是这些癌症绕过宿主细胞抗癌机制的能力以及某些癌症对化疗药物迅速产生耐药性的原因。我们将开展以下研究：1)我们将使用我们的新的双链DNA测序方法来量化亚克隆突变的数量，以此作为单个癌症的增殖、侵袭和转移能力的函数；2)我们将确定由于DNA复制的保真度降低或DNA修复效率降低而导致的特定类型的突变是否会改变癌症细胞的适合性；以及3)我们将使用这种超精确的方法来确定亚克隆DNA突变是否可以用作预后生物标记物。对肿瘤内突变异质性的程度和来源的了解可能会极大地影响我们对疾病的评估，并极大地促进全面的个性化化疗的实施。