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

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早发性乳腺癌和结肠癌有关。这将通过对非裔美国人和白种人的肿瘤进行外显子组测序，确定基因型组合，并比较两组患者之间的体细胞突变率来实现。我们将利用外显子捕获和高通量配对端测序技术鉴定160个肿瘤的外显子体细胞突变，这些突变代表TP53 Pro/Pro vs Arg/Arg基因型和MDM2 SNP309 T/T vs G/G基因型的四种组合。这样就可以得出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，并且可以确定两个种族之间突变率的差异是否可以归因于这两个基因座的遗传差异。基因型和表型之间的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等基因组来测试，并仔细检查修饰后的细胞是否增加或减少了tp53依赖性的细胞周期阻滞、凋亡或突变率。

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.