Molecular Genomics of Breast Cancer

乳腺癌的分子基因组学

• 批准号: 7266355
• 负责人: Sergei R Malkhosyan
• 金额: $ 55.58万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266355
• 关键词: 8q24; Archives; Behavior; Breast; Cells; Characteristics; Chromosome Deletion; Chromosome abnormality; Chromosomes; Collection; Correlation Studies; DNA copy number; Data; Detection; Development; Freezing; Frequencies; Gene Amplification; Gene Dosage; Genetic; Genetic Markers; Genome; Genomics; Goals; Laboratories; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Maps; Microsatellite Repeats; Molecular; Mutation; Neoplastic Cell Transformation; Numbers; Oncogenes; Paraffin; Pathologic; Pathway interactions; Patients; Phenotype; Play; Process; Recurrence; Resolution; Role; Site; Sorting - Cell Movement; Specimen; Staging; Subgroup; Techniques; Testing; Translating; Tumor Suppressor Genes; Xq25; breast cancer diagnosis; cancer cell; cancer diagnosis; cancer genome; cancer recurrence; cell growth; chromosome loss; comparative; density; follow-up; genetic profiling; malignant breast neoplasm; neoplastic cell; novel; outcome forecast; research study; trend; tumor; tumorigenesis

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(申请人提供)：细胞基因组的扭曲是肿瘤转化的特征。发生在肿瘤细胞中的基因改变导致细胞生长或存活的正向调节因子的激活，以及抑制这些过程的因素的失活。一种特殊类型的基因组改变，即染色体片段拷贝数失衡，在恶性转化中起着重要作用：染色体缺失可能会使抑癌基因失活，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，AP-PCR阵列的比较杂交(CHPA)，用于高分辨率的乳腺肿瘤DNA拷贝数改变的轮廓分析。这将允许在癌细胞基因组的数千个位置检测单个DNA拷贝数的丢失或增加(特定目标1)。我们推测，这些遗传信号可能包含哪些癌症基因负责每个肿瘤的发展和进展，从而导致肿瘤细胞的病理行为及其对治疗的反应性的信息。这一一般假设将通过分析基因图谱以根据肿瘤发生的途径(已知或新的)来区分乳腺肿瘤，并通过分析乳腺肿瘤的基因图谱与其临床病理特征、复发和患者的生存相关联来检验，以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，就会将它们与已知在乳腺癌发生中发挥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异常进行进一步鉴定，最终目标是确定潜在的新癌症基因(特定目标3)。这些实验将提供一个全面的观点，遗传异常在乳腺肿瘤发生中的作用。它们还将有助于识别乳腺癌诊断、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。