Chromosomal Aberrations in Epithelial/Hematologic Cancer

上皮/血液癌中的染色体畸变

• 批准号: 6558742
• 负责人: Thomas E. Ried
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6558742
• 关键词: adenoma; aneuploidy; blood /lymphatic neoplasm; carcinoma; chromosome aberrations; chromosome translocation; colorectal neoplasms; comparative genomic hybridization; cytogenetics; disease /disorder model; epithelioma; gene expression; genetic techniques; genetically modified animals; karyotype; laboratory mouse; metastasis; neoplasm /cancer classification /staging; neoplasm /cancer diagnosis; neoplasm /cancer genetics; ovary neoplasms; technology /technique development

The cytogenetic and molecular cytogenetic characterization of human solid tumors and hematological malignancies has revealed a non-random distribution of chromosomal aberrations. The complementary use of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) on the same tumors has provided ample evidence that the translocation induced activation of oncogenes is predominantly restricted to leukemias and lymphomas. The results of chromosomal aberrations in solid tumors of epithelial origin are genomic imbalances. Our research is focused on identifying clinically relevant translocations in hematological malignancies and exploring mechanisms and consequences of genomic imbalances in solid tumors. We intend to use SKY for the classification of acute myelogenous leukemia and for the identification of secondary chromosomal aberrations that correlate with resistance to therapy in patients with chronic myelogenous leukemia treated with the tyrosine kinase inhibitor STI571 and correlate the results with those from murine model systems of leukemias and lymphomas. The CGH analysis of more than 500 carcinomas in our laboratory has revealed that genomic imbalances as a result of unbalanced chromosomal translocations or chromosomal gains and losses are the premier cytogenetic event in solid tumors of epithelial origin. CGH analyses will be focused on colorectal adenomas, carcinomas, and metastases, and ovarian carcinomas. Their cytogenetic profiles will then be compared with gene expression analyses in order to further our understanding of the consequences of aneuploidy. Efforts to define the sequence of genetic aberrations during carcinogenesis, explain the biology of tumor progression and establish test systems for novel therapeutics depend increasingly on animal models of human cancer. Murine models of human carcinogenesis are widely used to delineate genetic mechanisms that determine tumor initiation and progression and improved methods for genetic manipulation open new avenues to study biological pathways of tumorigenesis. We have therefore devoted considerable effort to the development of molecular cytogenetic tools for the analyses of chromosomal aberrations in mouse models of human cancer. Karyotype analysis of chemically induced plasmacytomas in mice,11 in lymphomas from ATM or Ku80 deficient animals, and in mice transgenic for c-myc, has provided evidence for the conservation of mechanisms leading to chromosomal aberrations across species boundaries. Our development of molecular cytogenetic methods for the analysis of murine genomes allows us to further contribute to the validation of mouse models of human cancers.

人类实体瘤和血液系统恶性肿瘤的细胞遗传学和分子细胞遗传学特征揭示了染色体畸变的非随机分布。比较基因组杂交（CGH）和光谱核型分析（SKY）在相同肿瘤上的互补使用提供了充分的证据，证明易位诱导的癌基因激活主要限于白血病和淋巴瘤。上皮来源的实体瘤中染色体畸变的结果是基因组失衡。我们的研究重点是确定血液恶性肿瘤中临床相关的易位，并探索实体瘤中基因组失衡的机制和后果。我们打算使用SKY对急性骨髓性白血病进行分类，并识别与接受酪氨酸激酶抑制剂STI 571治疗的慢性骨髓性白血病患者的治疗耐药性相关的次级染色体畸变，并将结果与小鼠模型系统的结果相关联白血病和淋巴瘤。 我们实验室对500多例癌的CGH分析表明，由于染色体易位或染色体获得和丢失不平衡而导致的基因组不平衡是上皮来源的实体瘤中首要的细胞遗传学事件。CGH分析将集中在结直肠腺瘤、癌、转移瘤和卵巢癌。然后将其细胞遗传学谱与基因表达分析进行比较，以进一步了解非整倍体的后果。 确定致癌过程中遗传畸变序列、解释肿瘤进展的生物学和建立新疗法的测试系统的努力越来越依赖于人类癌症的动物模型。人类肿瘤发生的小鼠模型被广泛用于描述决定肿瘤发生和发展的遗传机制，改进的遗传操作方法为研究肿瘤发生的生物学途径开辟了新的途径。因此，我们投入了相当大的努力，发展分子细胞遗传学工具，用于分析人类癌症小鼠模型中的染色体畸变。化学诱导的小鼠浆细胞瘤，11 ATM或Ku 80缺陷动物的淋巴瘤，以及c-myc转基因小鼠的核型分析，提供了跨物种边界的染色体畸变的机制的保护的证据。我们开发的用于分析小鼠基因组的分子细胞遗传学方法使我们能够进一步促进人类癌症小鼠模型的验证。