PHENOTYPIC RISK MARKERS IN BRCA1 MUTATION CARRIERS

两种主要的乳腺癌易感基因BRCA1和BRCA2的鉴定预示着一个遗传风险评估的时代，这反过来又有助于促进在高危人群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悬而未决的问题涉及突变携带者在癌症发展、发病年龄和癌症类型方面观察到的广泛外显率。此外，它已经假设，但没有证明，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BRCA1突变的人可能比具有正常BRCA1基因拷贝的人更迅速、更广泛地积累其他遗传损伤迹象。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，需要更好地了解由于BRCA1基因遗传突变导致易感个体发生乳腺癌的遗传变化的中间途径，以及杂合个体对DNA损伤剂的易感性。在本提案中，我们将在染色体水平上表征BRCA1突变的表型表现。本提案的主题将涉及阐明BRCA1杂合突变细胞中基因组不稳定性的各种表现，目的是开发诊断测试以进一步评估风险，从而有助于制定治疗干预措施。染色体携带者的范围将在本研究中确定。我们将确定在外周血淋巴细胞中观察到的染色体不稳定性是否反映了乳腺上皮细胞的染色体不稳定性。在BRCA1突变携带者中，染色体不稳定性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节点。这将提供一种表型标记，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化潜力，从而可能影响降低风险的干预战略的制定。

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.