Wen Hongxiu, Kim Yeong C, Snyder Carrie, Xiao Fengxia, Fleissner Elizabeth A, Becirovic Dina, Luo Jiangtao, Downs Bradley, Sherman Simon, Cowan Kenneth H, Lynch Henry T, Wang San Ming
Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, USA.
BMC Cancer. 2014 Jun 26;14:470. doi: 10.1186/1471-2407-14-470.
Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family.
In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer.
We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation.
Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions.
遗传易感性是家族性乳腺癌的主要风险因素。然而，对于大多数家族性乳腺癌来说，其遗传易感性仍然未知。所有新发现的易感性在疾病人群中都很少见，据估计未知的遗传易感性总数可达数千种。家族单位是遗传学的基本结构。由于这是一种常染色体显性疾病，有家族性乳腺癌病史的个体在几代人中必定携带相同的遗传易感性。因此，关注家族性乳腺癌谱系中的病例，而非疾病人群中的汇总病例，有望为识别每个家族的遗传易感性提供高概率。
在本研究中，我们通过分析家族性乳腺癌中家族特异性变异来检测遗传易感性。利用外显子组测序，我们分析了三个家族以及22名患有BRCAx（BRCA阴性）家族性乳腺癌的先证者。
我们在每个家族中都观察到了家族特异性的、新的、有害的种系变异。在已识别的种系变异中，许多变异在同一家族中受疾病影响的家族成员之间共享，但在不同家族中未发现，每个家族都有其自身的特异性变异。某些变异被认为是有害的遗传易感性，会损害参与DNA复制、损伤修复、肿瘤抑制、信号转导和磷酸化的功能重要基因。
我们的研究表明，许多BRCAx家族性乳腺癌家族的易感性可能存在于每个患病家族中。采用以家族为中心的方法有潜力检测到许多新的易感性。
