Cancer Risks in Multi-ethnic Carriers of Unclassified BRCA1 Variants

项目摘要 BRCA1基因蛋白失活突变与乳腺癌和卵巢癌的升高相关 风险。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一碱基变化，称为非同义未分类变体(ns UCV)。由于这些变种很少见，没有任何单一的数据来源能够提供足够的信息，从而明确地 将它们归类为中性或致病性。我们的目标是评估添加有用的新信息的可行性 通过评估一级亲属(FD)的癌症发病率来了解BRCA1的NSUCV的风险 以人群为基础的多种族系列乳腺癌发病病例的研究，这些病例有无无紫外线。我们的 具体目标是：1)比较在西班牙裔、亚裔和非裔美国人中检测到的新生儿脐带血病毒的患病率和类型。 美国人、非裔美国人和非西班牙裔白人(NHW)乳腺癌病例从 北加州乳腺癌家庭登记(Breast CFR)部分；2)估计风险比 以及66例携带UCV的FD亲属中BRCA1相关癌症的标准化残留物， 与1729例最多携带中性多态的病例进行比较；3)结合目标2的结果 根据现有的变异体的致病性评分将它们归类为良性或有害；以及4) 评估此分类与使用基于函数的统计学习获得的分类之间的一致性 算法。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。如果我们发现这个可行性研究的结果是 承诺，我们将寻求单独的资金，将其扩展到BRCA1和BRCA2的其他UCV，使用更大的 一系列以人群为基础的家庭来自乳房CFR和其他以人群为基础的乳房和卵巢 癌症家族登记处。项目叙事 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 经过广泛研究。这项研究将考察使用以下工具添加有关这些风险的新信息的可行性 来自变异携带者亲属的癌症数据。

Project Abstract 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. Project Narrative 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.