Molecular Genomics of Breast Cancer

乳腺癌的分子基因组学

• 批准号: 6887078
• 负责人: Sergei R Malkhosyan
• 金额: $ 56.81万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-17 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6887078
• 关键词: biotechnology; breast neoplasm /cancer diagnosis; breast neoplasms; chromosome aberrations; chromosome deletion; clinical research; comparative genomic hybridization; gene expression profiling; genetic mapping; genetic markers; human genetic material tag; human tissue; molecular genetics; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplastic growth; neoplastic transformation; nucleic acid repetitive sequence; oncogenes; prognosis; tumor suppressor proteins

DESCRIPTION (provided by applicant): Distortion of the cell genome characterizes neoplastic transformation. Genetic alterations that occur in tumor cells lead to activation of positive regulators of cell growth or survival and inactivation of factors that suppress these processes. A particular type of genomic alteration, chromosomal segment copy number imbalance, plays a significant role in malignant transformation: chromosomal deletions may inactivate tumor suppressor genes, while chromosomal segment amplifications may increase the gene dosage of oncogenes. In this study, we propose to apply a new technique, Comparative Hybridization of AP-PCR Arrays (CHAPA), which was developed in our laboratory, for high resolution profiling of breast tumors for DNA copy number alterations. This will allow the detection of single DNA copy number losses or gains at thousands of sites throughout the genome of the cancer cells (Specific Aim 1). We hypothesize that such genetic signatures may embrace the information on what cancer genes were responsible for the development and progression of each tumor and, consequently, the resulting pathologic behavior of tumor cells and their responsiveness to treatment. This general hypothesis will be tested by the analysis of genetic profiles to differentiate breast tumors according to their pathways of tumorigenesis (known or novel) and by the analysis of genetic profiles of breast tumors in association with their clinicopathologic characteristics, recurrence, and patient's survival to reveal genetic markers for cancer diagnosis and prognosis. Once frequent (common for independent tumors) genomic alterations have been identified, they will be compared with the loci known to play a role in breast cancer development. The genetic aberrations in chromosomal regions that do not contain known cancer genes will be selected for further characterization with the ultimate goal to identify the underlying novel cancer genes (Specific Aim 3). These experiments will provide a comprehensive view on the role of genetic aberrations in breast tumorigenesis. They will also help to identify genetic markers for breast cancer diagnosis, development, and prognosis and facilitate the identification, mapping, and eventual isolation of novel cancer genes.

描述（由申请方提供）：细胞基因组的畸变是肿瘤转化的特征。发生在肿瘤细胞中的遗传改变导致细胞生长或存活的正调节因子的激活和抑制这些过程的因子的失活。一种特殊类型的基因组改变，染色体片段拷贝数不平衡，在恶性转化中起着重要作用：染色体缺失可能会破坏肿瘤抑制基因，而染色体片段扩增可能会增加癌基因的基因剂量。 在这项研究中，我们建议应用一种新的技术，比较杂交的AP-PCR阵列（CHAPA），这是在我们的实验室开发的，用于高分辨率分析乳腺肿瘤的DNA拷贝数的改变。这将允许检测癌细胞基因组中数千个位点的单个DNA拷贝数损失或增加（特异性目标1）。 我们假设，这些遗传特征可能包含哪些癌症基因负责每个肿瘤的发展和进展的信息，因此，肿瘤细胞的病理行为及其对治疗的反应性。将通过分析遗传图谱来检验这一一般假设，以根据肿瘤发生途径（已知或新）区分乳腺肿瘤，并通过分析乳腺肿瘤的遗传图谱及其临床病理学特征、复发和患者生存期来揭示癌症诊断和预后的遗传标记。 一旦确定了频繁的（独立肿瘤常见的）基因组改变，将其与已知在乳腺癌发展中起作用的基因座进行比较。将选择不含已知癌症基因的染色体区域中的遗传畸变进行进一步表征，最终目的是识别潜在的新型癌症基因（特定目的3）。 这些实验将提供一个全面的看法遗传畸变的作用，在乳腺肿瘤的发生。它们还将有助于确定乳腺癌诊断，发展和预后的遗传标记，并促进新癌症基因的识别，定位和最终分离。