DNA REPAIR POLYMORPHISMS AND SPORADIC BREAST CANCER

DNA 修复多态性与散发性乳腺癌

• 批准号: 6378000
• 负责人: ANTHONY T YEUNG
• 金额: $ 12.61万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378000
• 关键词: DNA repair; breast neoplasms; female; genetic mapping; genetic polymorphism; genetic screening; human genetic material tag; neoplasm /cancer genetics

DESCRIPTION: (Applicant's Description) Several cancers are known to arise from genetic defects in DNA repair genes. We propose to test whether concurrent germline defects in base-excision DNA repair genes are associated with sporadic breast cancer. Our focus is on small genetic variations we call eSNPs, exon Single Nucleotide Polymorphisms, in the coding region and the flanking control regions in the exons of genes. Specific Aim 1 is to screen the germline DNA of hundreds of women, half with sporadic breast cancer, for the presence of eSNPs in base-excision repair genes, and to test for the association of these eSNPs with breast cancer. In Specific Aim 2, we propose to develop a novel methodology that can be used to rapidly screen for eSNPs in these genes in thousands of individuals. In base-excision repair, more than one enzyme is specific for a given DNA damage. We hypothesize that when deleterious germline eSNPs occur concurrently in different genes of base-excision repair enzymes, the repair efficiency would decrease and somatic mutation rates would rise, and lead to cancer. Breast cancer that originates from multiple germline defects may seem to be sporadic. Currently it is impractical to screen for eSNPs in tens of repair genes in thousands of individuals. Initially, we will focus on the T/G mismatch that arises from spontaneous deamination of 5-methyl-cytosine residues in the DNA. Seven base-excision repair genes that correct this mismatch will be screened for eSNPs. The genes are: TDG, MEDI (MBD4), APE, NTHLI, PCNA, FEN1, and POL . The eSNP detection method we will use is based on a mismatch-specific CEL I nuclease we discovered. We propose to use a new mismatch-specific property of CEL I to perform affinity selection of total eSNPs, and also to enable affinity subtraction to remove the common alleles of eSNPs. The end product will be a highly emiched eSNP collection specific for sporadic breast cancer. Our proposed procedure will lead to a complete database of common and rare eSNPs in these genes so that existing technologies can do mass genotyping studies.

描述：（申请人的描述） 已知几种癌症是由DNA修复基因的遗传缺陷引起的。 我们建议测试是否并发生殖缺陷的碱基切除DNA 修复基因与散发性乳腺癌有关。我们的重点是小 基因变异，我们称之为eSNPs，外显子单核苷酸多态性，在 基因外显子中的编码区和侧翼控制区。具体 目标1是筛选数百名女性的生殖系DNA，其中一半患有散发性乳腺癌。 乳腺癌，碱基切除修复基因中存在eSNP，以及 检测这些eSNPs与乳腺癌的关联。在具体目标2中， 我们建议开发一种新的方法， 这些基因中的eSNPs。在碱基切除修复中， 不止一种酶对给定的DNA损伤具有特异性。我们假设 当有害的生殖系eSNPs同时出现在不同的基因中时， 碱基切除修复酶，修复效率会降低， 突变率会上升，并导致癌症乳腺癌起源于 多个生殖系缺陷引起的疾病似乎是偶发的。目前它是 在成千上万的人中筛选数十个修复基因中的eSNP是不切实际的， 个体首先，我们将重点关注T/G失配， DNA中5-甲基-胞嘧啶残基的自发脱氨。七 将筛选纠正这种错配的碱基切除修复基因， eSNPs。这些基因是：TDG、MEDI（MBD 4）、APE、NTHLI、PCNA、FEN 1和POL。的 我们将使用的eSNP检测方法是基于错配特异性CEL I 我们发现的核酸酶。 我们建议使用一个新的特定于失配的属性： CEL I以执行总eSNP的亲和力选择，并且还使 亲和力减法以去除eSNP的共同等位基因。最终产品 将是散发性乳腺癌特异性的高度富集的eSNP集合。 我们提出的程序将导致一个完整的数据库，共同和罕见的 这些基因中的eSNPs，以便现有技术可以进行大规模基因分型 问题研究