Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.
Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.
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DOI：
10.1371/journal.pgen.1005633
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发表时间：
2015-12
期刊：
影响因子：
4.5
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Carbone M;Flores EG;Emi M;Johnson TA;Tsunoda T;Behner D;Hoffman H;Hesdorffer M;Nasu M;Napolitano A;Powers A;Minaai M;Baumann F;Bryant-Greenwood P;Lauk O;Kirschner MB;Weder W;Opitz I;Pass HI;Gaudino G;Pastorino S;Yang H
我们最近发现了一种由BRCA 1相关蛋白1（BAP 1）种系突变引起的遗传性癌症综合征，间皮瘤、葡萄膜黑色素瘤和其他癌症的发病率很高，55岁时的发病率很高。为了确定BAP 1癌症综合征的家族，我们筛选了具有多发性间皮瘤和黑色素瘤和/或多种癌症家族史的患者。我们确定了四个具有相同BAP 1突变的家庭：他们生活在美国各地，似乎没有相关性。通过结合家族史、分子遗传学和系谱学方法，我们发现了一个BAP 1癌症综合征家族，该家族有大约80，000个后代，核心成员为106个个体，其成员来自18世纪初出生于德国并移民到北美的一对夫妇。他们的后代遍布全国，突变携带者受到多种恶性肿瘤的影响。我们的数据表明，一旦先证者被确定，这些kinetics的扩展分析，使用基因组和家谱研究，以确定最近的共同祖先，使研究人员能够发现可能携带BAP 1突变的家庭的其他分支。利用这些知识，我们已经确定了携带BAP 1突变的该家族的新分支。我们还实施了早期检测策略，帮助在早期阶段识别癌症，当它们可以治愈（黑色素瘤）或更容易接受治疗（MM和其他恶性肿瘤）时。生殖系BAP 1突变导致癌症综合征，其特征在于间皮瘤（MM）、葡萄膜黑色素瘤和其他癌症的高发病率，以及非常高的转移率，因为所有携带BAP 1突变的个体在其一生中发展至少一种，通常是几种恶性肿瘤。通过筛选有多种癌症病史的MM患者，我们发现了四名据称无关的患者，他们共享相同的生殖系BAP 1突变。我们研究了BAP 1突变是否发生在“从头”突变的“热点”，或者这四名MM患者是否有共同的祖先。利用分子基因组学分析，我们发现它们是相关的。通过家谱研究，我们将他们的祖先追溯到18世纪初从德国移民到北美的一对夫妇;我们追踪了他们后代的后续移民，他们现在至少生活在美国的三个不同州。我们的研究结果表明，BAP 1突变在几个世纪的时间里在后代中传播。这些知识和方法正被用于鉴定携带BAP 1突变的家族的其他分支。我们的研究表明，现代基因组分析的应用，加上治疗医生收集的“经典”家族史，以及家谱搜索，提供了一个强大的策略来识别高风险的生殖系BAP 1突变携带者，这将受益于遗传咨询和早期发现癌症筛查。
We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies). Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives. Through screening MM patients with histories of multiple cancers, we found four supposedly unrelated patients that shared an identical germline BAP1 mutation. We investigated whether this BAP1 mutation occurred in a ‘hot-spot’ for “de novo” mutations or whether these four MM patients shared a common ancestor. Using molecular genomics analyses we found that they are related. By genealogic studies we traced their ancestor to a couple that emigrated from Germany to North America in the early 1700’s; we traced the subsequent migration of their descendants, who are now living in at least three different US States. Our findings demonstrate that BAP1 mutations are transmitted among subsequent generations over the course of centuries. This knowledge and methodology is being used to identify additional branches of the family carrying BAP1 mutations. Our study shows that the application of modern genomic analyses, coupled with “classical” family histories collected by the treating physician, and with genealogical searches, offer a powerful strategy to identify high-risk germline BAP1 mutation carriers that will benefit from genetic counseling and early detection cancer screening.