Molecular Genomics of Breast Cancer

乳腺癌的分子基因组学

• 批准号: 7113819
• 负责人: Sergei R Malkhosyan
• 金额: $ 55.57万
• 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/7113819
• 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（由申请人提供）：细胞基因组的失真表征了肿瘤转化。肿瘤细胞中发生的遗传改变会导致细胞生长或存活的正调节剂激活抑制这些过程的因素。特定类型的基因组改变，染色体段拷贝数不平衡在恶性转化中起着重要作用：染色体缺失可能使肿瘤抑制基因失活，而染色体段的扩增可能会增加Oncogenes的基因剂量。 在这项研究中，我们建议在我们的实验室中开发的一种新技术，AP-PCR阵列（CHAPA）的比较杂交，以对乳腺肿瘤进行高分辨率分析，以进行DNA拷贝数改变。这将允许在整个癌细胞基因组中的数千个地点检测到单个DNA拷贝数损失或收益（特定AIM 1）。 我们假设这种遗传特征可能包含有关癌症基因的信息，导致每个肿瘤的发育和进展，从而导致肿瘤细胞的病理行为及其对治疗的反应。通过分析遗传谱分析乳腺肿瘤的肿瘤发生途径（已知或新颖），以及分析乳腺肿瘤的遗传特征与其临床病理学特征，复发和患者的存活，以揭示癌症诊断和预测的遗传标记。 一旦发现了经常（常见于独立肿瘤）的基因组改变，它们将与已知在乳腺癌发育中起作用的基因座进行比较。将选择不包含已知癌症基因的染色体区域的遗传像差，以进一步表征以识别潜在的新型癌症基因的最终目标（特定目标3）。 这些实验将对遗传像差在乳腺肿瘤发生中的作用提供全面的看法。它们还将有助于确定用于乳腺癌诊断，发育和预后的遗传标志物，并促进新型癌症基因的鉴定，映射和最终分离。