A Genetic Model for Early-Onset Breast and Colon Cancer in African Americans

非裔美国人早发乳腺癌和结肠癌的遗传模型

基本信息

批准号：
8389392
负责人：
FRED BUNZ
金额：
$ 34.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2013-03-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8389392
关键词：
African American Age Aging Alleles American Apoptosis Arginine Binding Binding Sites Breast Cancer Cell Cancer cell line Cell Cycle Arrest Cells ChIP-seq Chromatin Chromatin Structure Codon Nucleotides Colon Carcinoma Complex DNA Damage DNA Sequence Diagnosis Diagnostic Early Diagnosis Environmental Exposure European Event Exposure to Female breast Fibroblasts Future Gatekeeping Gene Expression Profile Gene Mutation Gene Targeting Gene-Modified Genes Genetic Genetic Models Genetic Polymorphism Genetic Transcription Genotype Guidelines Human Individual Left Life Link Longevity MDM2 gene Malignant Neoplasms Modality Modeling Mutation Oncogenes PRDM1 gene Pathway interactions Patients Phenotype Pilot Projects Polycomb Population Heterogeneity Probability Proline Protein p53 RNA Sequences Race Recruitment Activity Rest Risk Role Screening for cancer Screening procedure Somatic Mutation Stem cells TP53 gene Technology Testing Tumor Suppression Tumor Suppressor Genes Variant Work Writing advanced disease arginyl-prolyl-proline arginylarginine arginylproline base cancer cell cancer health disparity cancer risk caucasian American colon cancer cell line early onset exome genome-wide health disparity high risk keratinocyte malignant breast neoplasm normal aging novel prolyl-proline response stem cell differentiation tool tumor

项目摘要

DESCRIPTION (provided by applicant): This project seeks to determine whether polymorphisms in the TP53 and MDM2 genes are responsible for early-onset breast and colon cancer in African Americans. This will be accomplished by cancer exome sequencing of tumors from African Americans and Caucasian Americans with defined combinations of genotypes, and comparing the somatic mutation rates between the groups of patients. We will utilize exome capture and high- throughput paired-end sequencing technologies to identify exonic somatic mutations in 160 tumors representing the four combinations of TP53 Pro/Pro vs Arg/Arg genotypes and MDM2 SNP309 T/T vs G/G genotypes. This will allow correlations to be drawn between the numbers and types of somatic mutations, and race, TP53 genotype, and MDM2 genotype, and it will permit the determination of whether differences in mutation rates between the two races can be attributed to the genetic differences at these two loci. The existence of a cause and effect relationship between genotype and phenotype will be tested by constructing isogenic sets of breast and colon cancer cell lines that represent these four genotype combinations and carefully examining the modified cells for augmented or diminished TP53-dependent cell cycle arrest, apoptosis, or mutation rate. PUBLIC HEALTH RELEVANCE: African Americans are diagnosed with breast and colon cancer at early ages more frequently than are Caucasian Americans, however the reasons are not clear. This work will formally prove whether or not specific DNA sequences, which are more common in African Americans than in Caucasian Americans, can pre- dispose individuals to early onset breast or colon cancer, regardless of their race. If the hypothesis put forth in this proposal is validated, these results will provide the basis for identifying individuals that are at high risk for developing breast or colon cancer, and justify deploying more aggressive screening guidelines for those harboring high-risk DNA sequences.

描述（由申请人提供）：该项目旨在确定 TP53 和 MDM2 基因的多态性是否与非裔美国人的早发乳腺癌和结肠癌有关。这将通过对非裔美国人和白种人美国人的肿瘤进行癌症外显子组测序以及确定的基因型组合来实现，并比较各组患者之间的体细胞突变率。我们将利用外显子组捕获和高通量双端测序技术来鉴定 160 个肿瘤中的外显子体细胞突变，这些肿瘤代表 TP53 Pro/Pro 与 Arg/Arg 基因型和 MDM2 SNP309 T/T 与 G/G 基因型的四种组合。这将允许绘制体细胞突变的数量和类型与种族、TP53 基因型和 MDM2 基因型之间的相关性，并且将允许确定两个种族之间突变率的差异是否可以归因于基因差异这两个基因座。基因型和表型之间是否存在因果关系将通过构建代表这四种基因型组合的乳腺癌和结肠癌细胞系的同基因组并仔细检查修饰的细胞以增强或减弱TP53依赖性细胞周期停滞、细胞凋亡来测试，或突变率。公共卫生相关性：非裔美国人在早期被诊断出患有乳腺癌和结肠癌的频率高于白人美国人，但原因尚不清楚。这项工作将正式证明，特定的 DNA 序列（在非裔美国人中比在白种人美国人中更常见）是否会使个体更容易患上早发性乳腺癌或结肠癌，无论其种族如何。如果本提案中提出的假设得到验证，这些结果将为识别处于以下位置的个人提供基础：患乳腺癌或结肠癌的高风险，并证明对那些含有高风险 DNA 序列的人采取更积极的筛查指南是合理的。