PHENOTYPIC RISK MARKERS IN BRCA1 MUTATION CARRIERS

BRCA1 突变携带者的表型风险标记

• 批准号: 6489436
• 负责人: GAIL ELIZABETH TOMLINSON
• 金额: $ 7.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-22 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489436
• 关键词: brca gene; breast neoplasms; cancer risk; clinical research; family genetics; female; gene mutation; genetic carriers; genetic markers; human subject; neoplasm /cancer genetics; phenotype; tissue /cell culture; women's health

The identification of the two major breast cancer predisposition genes, BRCA1 and BRCA2, has heralded an era of genetic risk assessment which in turn has helped to facilitate the development of new strategies for early detection and prevention of breast cancer in the high-risk individual. However remaining unanswered questions regarding genetic risk assessment involve the wide range of penetrance observed in mutation carriers with respect to incidence of cancer development, age of onset and cancer type. In addition, it has been hypothesized but not proven that additional inherited genetic traits as well as environmental factors modulate the effect of a BRCA1 or BRCA2 mutation. The BRFFCA1 gene is now known to play a role in DNA repair. It is hypothesized that persons who carry a mutation of BRCA1 may be at risk of accumulating other signs of genetic damage more rapidly and more extensively than individuals with normal copies of the BRCA1 genes. This end result of this accumulation of genetic damage is the development of breast cancer at an early stage. In order to ultimately reduce breast cancer mortality due to inherited mutation of the BRCA1 gene, a better understanding is needed of the intermediate pathways of due to inherited mutation of the BRCA1 gene, a better understanding is needed of the intermediate pathways of genetic change leading to breast cancer in the predisposed individual along with a better understanding of the susceptibility of the heterozygous individual to DNA damaging agents. In this proposal we will characterize on a chromosomal level the phenotypic manifestation of BRCA1 mutations. The theme of this proposal will involve the elucidation of various manifestations of genomic instability in cells that are heterozygously mutant for BRCA1, with the goal of developing diagnostic tests to further assess risk which will then assist in making therapeutic interventions. The extent of chromosomal carriers will be determined in this study. We will determine if chromosomal instability observed in peripheral blood lymphocytes is reflective of chromosomal instability in breast epithelial cells. The degree of chromosomal instability will be correlated with the development of cancer in BRCA1 mutation carriers. We will determine if occasional loss of alleles in susceptible tissue is a marker of risk. This study targets key points in the pathway of tumor development and progression in BRCA1 mutation carriers. This will provide a phenotypic marker, which may be useful in refining cancer risk assessment in the BRCA1 mutation carrier. This will have the translational potential for developing new diagnostic tests, which may then influence the development of intervention strategies to reduce risk.

两个主要的乳腺癌易感基因BRCA1和BRCA2的发现，预示着一个遗传风险评估的时代的到来，这反过来又有助于促进在高危个体中早期发现和预防乳腺癌的新策略的发展。然而，关于遗传风险评估的其余未回答的问题涉及在突变携带者中观察到的关于癌症发展的发生率、发病年龄和癌症类型的广泛的突变率。此外，它已被假设，但未被证明，额外的遗传性状以及环境因素调节BRCA1或BRCA2突变的影响。目前已知BRFFCA1基因在DNA修复中发挥作用。据推测，携带BRCA 1突变的人可能比BRCA 1基因拷贝正常的人更快、更广泛地积累其他遗传损伤迹象。这种遗传损伤积累的最终结果是早期乳腺癌的发展。为了最终降低由于BRCA 1基因的遗传突变导致的乳腺癌死亡率，需要更好地理解由于BRCA 1基因的遗传突变导致的中间途径，需要更好地理解导致易感个体中乳腺癌的遗传变化的中间途径，同时沿着更好地理解杂合个体对DNA损伤剂的易感性。在这个提议中，我们将在染色体水平上表征BRCA1突变的表型表现。 该提案的主题将涉及阐明BRCA 1杂合突变细胞中基因组不稳定的各种表现，目标是开发诊断测试以进一步评估风险，然后协助进行治疗干预。本研究将确定染色体携带者的范围。我们将确定在外周血淋巴细胞中观察到的染色体不稳定性是否反映了乳腺上皮细胞中的染色体不稳定性。染色体不稳定的程度将与BRCA1突变携带者的癌症发展相关。我们将确定易感组织中等位基因的偶尔丢失是否是风险的标志。这项研究的目标是BRCA1突变携带者肿瘤发生和进展途径中的关键点。这将提供一个表型标记，这可能有助于改善BRCA1突变携带者的癌症风险评估。这将具有开发新的诊断测试的转化潜力，然后可能影响干预策略的制定以降低风险。