Cancer Risks in Multi-ethnic Carriers of Unclassified BRCA1 Variants

描述（由申请人提供）：BRCA1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，其他BRCA1变异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异（ns ucv）。由于这些变异是罕见的，没有任何单一的数据来源能够提供足够的信息来明确地将它们分类为中性或致病性。我们的目标是通过评估以人群为基础的多种族系列的有或无ns ucv的乳腺癌病例的一级亲属的癌症发病率，来评估增加关于BRCA1的ns ucv风险的有用新信息的可行性。我们的具体目的是：1)比较从乳腺癌家庭登记处（breast CFR）北加州组成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人（NHW）乳腺癌病例中检测到的nsucv的患病率和类型；2)估计66例携带ns ucv的FD亲属与1729例携带大多数中性多态性的FD亲属相比brca1相关癌症的风险比和标准化残差；3)将Aim 2的结果与变异的现有致病性评分相结合，将其分类为良性或有害；4)评估该分类与使用基于函数的统计学习算法得到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分类疾病易感基因中的其他变异的潜力。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BRCA1和BRCA2的其他ucv，使用来自乳腺CFR和其他基于人群的乳腺癌和卵巢癌家族登记处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异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。这项研究将检验利用变异携带者亲属的癌症数据增加这些风险新信息的可行性。

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.