Cancer Risks in Multi-ethnic Carriers of Unclassified BRCA1 Variants

描述(由申请人提供)：BRCA1基因的蛋白质失活突变与乳腺癌和卵巢癌风险增加有关。然而，对于其他BRCA1变体的影响仍有相当大的不确定性，特别是改变蛋白质氨基酸的单碱基变化，称为非同义非分类变体(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归类为中性或致病。我们的目标是通过评估一组基于人群的多种族乳腺癌病例的一级亲属(FD)的癌症发病率，评估添加有关BRCA1的NSUCVs风险的有用新信息的可行性。我们的具体目标是：1)比较在从乳腺癌家庭登记(Breast CFR)的北加州部分确定的西班牙裔、亚裔美国人、非裔美国人和非西班牙裔白人(NHW)乳腺癌病例中检测到的NSUCVs的患病率和类型；2)估计66例携带NSUCVs的FD亲属中BRCA1相关癌症的风险比和标准化残留物，与1729例携带NSUCVs的病例相比；3)结合目标2的结果和变异体的可用致病性评分，将它们归类为良性或有害的；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可能性。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，将其扩展到其他BRCA1和BRCA2的UCVs，使用来自乳腺疾病预防控制中心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庭。与已建立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，特别是对西班牙裔和非白人人群，他们的风险尚未得到广泛研究。这项研究将研究使用变异携带者亲属的癌症数据添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.