BRCA2 missense mutations and breast cancer

描述（由申请人提供）：无法确定与BRCA 1和BRCA 2基因中大多数错义突变相关的癌症风险。因此，当在临床测试期间在BRCA 1或BRCA 2乳腺癌和卵巢癌易感基因中鉴定出错义突变时，具有突变的患者和患者的家庭成员不能从改善的风险评估中受益。解释BRCA 1和BRCA 2中1,600个已知的错义突变是否易患癌症的困难源于这些突变对BRCA 1和BRCA 2功能的不确定影响。本提案中要解决的假设是，使用遗传学、流行病学和分子生物学方法的组合，可以将BRCA 1和BRCA 2基因中的错义突变定义为癌症易感性或无临床意义。BRCA 1 BRCT结构域和BRCA 2 DNA结合结构域中的错义突变将使用（A）基于突变与癌症的共分离、突变与其它有害突变的共发生以及携带这些突变的家族中癌症的家族史概况的错义突变的癌症因果关系的似然模型;（B）功能测定;（C）进化序列保守性分析;和（D）利用A）- C）中产生的数据的双组分混合物模型。每种方法将用于评估这些结构域的错义突变，并独立预测哪些突变是有害的或中性的。这些数据也将在双组分混合物模型中组合，以生成每种错义突变的癌症相关性的组合估计值，并鉴定对错义突变分类最有价值的测定/方法。重要的是，一旦结合遗传/家族数据确定了一些更常见突变的功能测定和序列保守方法的灵敏度和特异性，即使在缺乏遗传数据的情况下，也可以使用这些测定来确定BRCA 1和BRCA 2这些结构域中其他罕见错义突变的癌症相关性。在研究结束时，许多错义突变的癌症相关性将被确定，并提供给携带者，他们将能够从改善的癌症风险评估、癌症预防甚至治疗策略中受益。

DESCRIPTION (provided by applicant): The risk of cancer associated with most missense mutations in the BRCA1 and BRCA2 genes cannot be determined. Thus, when a missense mutation is identified in the BRCA1 or BRCA2 breast and ovarian cancer predisposition genes during clinical testing, the patient with the mutation and the patient's family members cannot benefit from improved risk assessment. The difficulty in interpreting whether the 1,600 known missense mutations in BRCA1 and BRCA2 predispose to cancer stems from the undefined influence of these mutations on BRCA1 and BRCA2 function. The hypotheses to be addressed in this proposal is that missense mutations in the BRCA1 and BRCA2 genes can be defined as either cancer predisposing or of no clinical significance using a combination of genetic, epidemiological and molecular biological approaches. Missense mutations in the BRCA1 BRCT domains and the BRCA2 DNA binding domain will be characterized using (A) a likelihood model of cancer causality for missense mutations based on co- segregation of the mutations with cancer, co-occurrence of the mutations with other deleterious mutations, and on the family history profile of cancer in families carrying these mutations; (B) functional assays; (C) evolutionary sequence conservation analysis; and (D) a two-component mixture model that utilizes the data generated in A) - C). Each method will be used to evaluate missense mutations from these domains and to independently predict which mutations are deleterious or neutral. These data will also be combined in the two-component mixture model to generate a combined estimate of the cancer relevance of each missense mutation and to identify the assays/approaches that are most valuable for classifying missense mutations. Importantly, once the sensitivity and specificity of the functional assays and sequence conservation method have been determined for some of the more common mutations in conjunction with the genetic/family data it will then be possible to use these assays to define the cancer relevance of other rare missense mutations in these domains of BRCA1 and BRCA2, even in the absence of genetic data. At the conclusion of the study the cancer relevance of many missense mutations will have been determined and provided to the carriers who will then be able to benefit from improved cancer risk assessment, cancer prevention and perhaps even therapeutic strategies