Cancer Risks in Multi-ethnic Carriers of Unclassified BRCA1 Variants

描述（申请人提供）：BRCA 1基因的蛋白失活突变与乳腺癌和卵巢癌风险升高相关。然而，对于其他BRCA 1变体的影响存在相当大的不确定性，特别是改变蛋白质氨基酸的单碱基变化，称为非同义未分类变体（ns UCV）。由于这些变异是罕见的，没有一个单一的数据来源是足够的信息，明确地将它们归类为中性或致病性。我们的目标是通过评估一个基于人群的多种族系列乳腺癌病例（有和无ns UCV）的一级（FD）亲属的癌症发病率，评估增加关于BRCA 1 ns UCV风险的有用新信息的可行性。我们的具体目标是：1）比较从乳腺癌家族登记的加州北方部分确定的西班牙裔、亚裔美国人、非洲裔美国人和非西班牙裔白色（NHW）乳腺癌病例中检测到的ns UCV的患病率和类型（乳腺CFR）; 2）估计66例携带ns UCV的FD亲属中BRCA 1相关癌症的危险比和标准化残差，与最多携带中性多态性的1729例病例的那些进行比较; 3）将Aim 2的联合收割机结果与变体的可用致病性评分相结合，以将它们分类为良性或有害;以及4）评估该分类与使用基于函数的统计学习算法获得的分类之间的一致性。我们的最终目标是评估利用携带者亲属的癌症发病率来帮助对疾病易感基因的其他变异进行分类的潜力。如果我们发现这项可行性研究的结果是有希望的，我们将寻求单独的资金将其扩展到BRCA 1和BRCA 2的其他UCV，使用来自乳腺癌CFR和其他基于人群的乳腺癌和卵巢癌家族登记的更大系列的基于人群的家族。与已确定的疾病易感基因的未分类变体相关的风险具有重要的临床意义，特别是对于西班牙裔和非白人人群，其风险尚未得到广泛研究。这项研究将探讨使用变异携带者亲属的癌症数据增加有关这些风险的新信息的可行性。

DESCRIPTION (provided by applicant): Protein inactivating mutations of the BRCA1 gene are associated with elevated breast and ovarian cancer risks. However there is considerable uncertainty about the effects of other BRCA1 variants, particularly the single base changes that alter amino acids of the protein, termed nonsynonymous unclassified variants (ns UCVs). Because these variants are rare, no single source of data is sufficiently informative to unambiguously classify them as either neutral or pathogenic. Our goal is to assess the feasibility of adding useful new information about the risks of ns UCVs of BRCA1 by assessing cancer incidence in first-degree (FD) relatives of a population-based multi-ethnic series of incident breast cancer cases with and without ns UCVs. Our specific aims are: 1) to compare the prevalence and types of ns UCVs detected among Hispanic, Asian- American, African-American and non-Hispanic white (NHW) breast cancer cases ascertained from the Northern California component of the Breast Cancer Family Registry (Breast CFR); 2) to estimate risk ratios and standardized residuals for BRCA1-related cancers among FD relatives of 66 cases who carry ns UCVs, compared to those of 1729 cases who carry at most neutral polymorphisms; 3) to combine results of Aim 2 with available pathogenicity scores of the variants to classify them as benign or deleterious; and 4) to evaluate agreement between this classification and one obtained using a function-based statistical learning algorithm. Our ultimate goal is to assess the potential of using cancer incidence in relatives of carriers to help classify other variants in disease-susceptibility genes. If we find that the results of this feasibility study are promising, we will seek separate funding to extend it to other UCVs of BRCA1 and BRCA2, using a larger series of population-based families from the Breast CFR and other population-based breast and ovarian cancer family registries. The risks associated with unclassified variants of established disease-susceptibility genes have important clinical implications, particularly for Hispanic and nonwhite populations, whose risks have not been extensively studied. This study will examine the feasibility of adding new information about these risks using cancer data from relatives of variant carriers.