Mutator Phenotype in Human Cancers

人类癌症中的突变表型

• 批准号: 8094346
• 负责人: LAWRENCE A LOEB
• 金额: $ 28.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094346
• 关键词: Accounting; Base Sequence; Biological Assay; Blast Phase; Cancer Patient; Cells; Chromosome abnormality; Chronic Myeloid Leukemia; Colon Carcinoma; DNA; DNA Sequence; Data; Detection; Drug resistance; Evolution; Exhibits; Exons; Frequencies; Genes; Genetic; Genome; Heterogeneity; Human; Interphase Cell; Introns; Invaded; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Manuscripts; Measures; Minority; Mitochondria; Mitochondrial DNA; Monitor; Mutagenesis; Mutation; Neoplasm Metastasis; Normal tissue morphology; Nuclear; Nucleotides; Phenotype; Point Mutation; Population; Prostatic Neoplasms; Protocols documentation; Recurrence; Reporter; Resistance; Serum; Time; Tissues; Treatment outcome; Tumor Markers; base; cancer cell; chemotherapy; clinically significant; human tissue; indexing; mitochondrial DNA mutation; mutant; neoplastic cell; prevent; prognostic indicator; research study; resistance mutation; response; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The objective of this proposal is to determine the frequency and types of random mutations in normal and malignant human cells. Our hypothesis is that normal mutation rates are insufficient to account for the multiple mutations observed in cancers and that cancer cells exhibit a mutator phenotype. Normal human cells are able to copy their genomes with only one, or at most a few, mistakes during each division cycle. In contrast, cancer cells exhibit large numbers of chromosomal aberrations and we postulate that they may harbor hundreds to thousands of additional, random changes in DNA sequence. Large numbers of random mutations (i.e., mutations that occur in one or only a few cells of a tumor) could contribute to tumor progression, and could account for the heterogeneity of cancer cells within a tumor, the rapid emergence of resistance to chemotherapy, and the ability of cancer cells to invade adjacent tissues and to metastasize. Quantitation of random mutation frequency in tumors may be useful in stratifying cancers, providing an index of tumor heterogeneity, and prognosticating malignant and metastatic potential and treatment outcome. We have established an assay that can detect one nucleotide substitution when present in one hundred million correct nucleotides. Our protocol allows us to measure the frequency of random changes in nucleotide sequence in introns and exons, and in dividing and non-dividing cells. We will use our assays to examine nucleotide changes in nuclear DNA from different normal human tissues, in different human cancers, and in human cells in culture. We will measure changes in mitochondrial DNA in prostatic cancers in relationship to tumor grade. If increases in mutation frequency drive tumor progression, it is extremely important to identify agents that can inhibit mutagenesis and thereby prevent or impede the progression of human cancers.

描述（由申请人提供）：该提案的目的是确定正常和恶性人类细胞中随机突变的频率和类型。我们的假设是，正常突变率不足以说明癌症中观察到的多重突变，并且癌细胞表现出突变器表型。正常的人类细胞能够在每个分区周期中仅使用一个或最多的错误来复制其基因组。相比之下，癌细胞表现出大量染色体畸变，我们假设它们可能携带数百至数千到数千到数以千计的DNA序列随机变化。大量的随机突变（即发生在肿瘤的一个或仅几个细胞中的突变）可能有助于肿瘤进展，并且可以解释肿瘤内癌细胞的异质性，对化疗的耐药性快速出现以及癌细胞侵入邻近组织和转移的能力。肿瘤中随机突变频率的定量可能有助于分层癌症，提供肿瘤异质性指数，并预测恶性和转移性潜力和治疗结果。我们已经建立了一个测定法，可以在一亿正确的核苷酸中存在一个核苷酸取代。我们的协议使我们能够测量内含子和外显子中核苷酸序列中随机变化的频率，以及分裂和非分散细胞的频率。我们将使用我们的测定法检查来自不同正常人体组织，不同人类癌症和培养物中人类细胞中核DNA中核苷酸的变化。我们将测量前列腺癌中线粒体DNA与肿瘤等级的变化。如果突变频率驱动肿瘤的进展，那么确定可以抑制诱变并防止或阻碍人类癌症进展的药物非常重要。