PHENOTYPIC RISK MARKERS IN BRCA1 MUTATION CARRIERS

两个主要的乳腺癌易感基因BRCA1和BRCA2的发现预示着遗传风险评估时代的到来，这反过来又有助于开发新的策略，以早期发现和预防高危个体的乳腺癌。然而，关于遗传风险评估的仍未回答的问题涉及在突变携带者中观察到的关于癌症发生发生率、发病年龄和癌症类型的广泛外显性。此外，已经提出了假设，但没有得到证实，额外的遗传遗传特征以及环境因素调节了BRCA1或BRCA2突变的影响。BRFFCA1基因现在已知在DNA修复中发挥作用。据推测，携带BRCA1突变的人可能比携带正常BRCA1基因的人更快、更广泛地积累其他遗传损害的迹象。这种基因损伤积累的最终结果是早期乳腺癌的发展。为了最终降低BRCA1基因遗传突变导致的乳腺癌死亡率，需要更好地了解BRCA1基因遗传突变导致乳腺癌的中间途径，需要更好地了解导致乳腺癌易感个体的基因变化的中间途径，以及杂合子个体对DNA损伤剂的易感性。在这项建议中，我们将在染色体水平上描述BRCA1突变的表型表现。这项建议的主题将涉及阐明BRCA1杂合突变的细胞中基因组不稳定的各种表现，目的是开发诊断测试以进一步评估风险，然后帮助进行治疗干预。染色体携带者的范围将在这项研究中确定。我们将确定在外周血淋巴细胞中观察到的染色体不稳定是否反映了乳腺上皮细胞中的染色体不稳定。在BRCA1突变携带者中，染色体不稳定的程度将与癌症的发展相关。我们将确定易感组织中偶尔丢失的等位基因是否是风险的标志。本研究针对BRCA1突变携带者肿瘤发生发展途径中的关键点。这将提供一个表型标记，这可能有助于改进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换潜力，然后可能会影响降低风险的干预策略的发展。

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.