GENETIC ANALYSIS USING THE GILDA RADNER REGISTRY

BRCA1基因突变被认为与至少70%的 卵巢癌和乳腺癌发病率过高的家庭。一点儿 已知剩余乳腺癌/卵巢癌的易感基因 家庭，或卵巢癌过多但很少或没有的家庭 乳腺癌。现在识别其他易感基因是可行的 治疗卵巢癌。这一努力的关键是来自许多大公司的DNA 卵巢癌家族。因为这样的家庭很少见，吉尔达·拉德纳 家族性卵巢癌登记是此类研究的重要资源。 该登记处于1981年在罗斯威尔公园癌症中心成立， 目前由大约1000个美国家庭组成，其中至少有两个 在一级或二级亲属中被诊断为卵巢癌。我们 建议确定100个信息最丰富的家庭以获取血液 和/或用于遗传连锁分析的档案组织标本。我们会 解决以下问题：i)卵巢癌占多少比例 家族中有BRCA1基因吗？2)有哪些流行病学特征(例如 平均发病年龄、种族、组织学亚型或恶性潜能 肿瘤，其他特定部位的癌症发生)与 没有联系的家庭？Iii)无关联的家系是否显示与其他基因座连锁？ 如果，就像几乎可以肯定的那样，BRCA1基因在项目中被克隆 期间，我们也会研究其他相关疾病的谱系。 有特定的BRCA1突变，并评估哪种流行病学 特征区分罹患癌症的突变携带者和 那些不这样做的人。为了实现这些目标，我们将挑选约260名 有三个或三个以上已报告卵巢癌的家庭和接触者 家庭成员填写家谱并核实已报告的癌症 对照医疗记录。然后我们将选出100个信息量最大的 并从以下地点获取血液和/或档案组织样本 受影响成员及受影响成员的一级亲属。最后， 我们将从血液样本中分离出有活性的淋巴细胞和DNA并分析 候选基因的连锁和突变样本。使用这个 大型注册中心绘制卵巢癌易感基因图谱和 描述在不同位置相连的家庭提供了这些好处：它 将确定哪些具有遗传高危的女性可以成为目标 筛查和干预，将允许对卵巢进行分类 癌症的基因亚型，从而促进病因学的研究 因素以及筛查和预防战略的规划。

Mutations of the BRCA1 gene are thought to be involved in at least 70% of families with excess incidence of cancers of the ovary and breast. Little is known about predisposing genes in the remaining breast/ovarian cancer families, or in families with excess ovarian cancer but little or no breast cancer. It is now feasible to identify other predisposing genes for ovarian cancer. Critical to this effort is DNA from many large ovarian cancer families. Because such families are rare, the Gilda Radner familial Ovarian Cancer Registry is an important resource for such study. The Registry, established at the Roswell Park Cancer Center in 1981, currently comprises some 1000 U.S. families containing at least two ovarian cancer diagnoses among first- or second-degree relatives. We propose to identify 100 of the most informative families to obtain blood and/or archival tissue specimens for genetic linkage analysis. We will address the following questions: i) What proportion of ovarian cancer families are due to the BRCA1 gene? ii) What epidemiologic features (e.g. mean age at onset, ethnicity, histologic subtype or malignant potential of tumor, other site-specific cancer occurrence) distinguish linked from unlinked families? iii) Do unlinked families show linkage to other loci? If, as seems almost certain, the BRCA1 gene is cloned within the project period, we also will examine the spectrum of other diseases associated with specific BRCA1 mutations, and assess which epidemiologic characteristics distinguish mutation carriers who develop cancer from those who do not. To accomplish these aims, we will select some 260 families containing three or more reported ovarian cancers and contact family members to complete the pedigrees and verify reported cancers against medical records. We then will select 100 of the most informative of these families and obtain blood and/or archival tissue specimens from affected members and first-degree relatives of affected members. Finally, we will isolate viable lymphocytes and DNA from blood samples and analyze the specimens for linkage and mutations in candidate genes. Use of this large registry to map predisposing genes for ovarian cancer and characterize families linked at different loci offers these benefits: it will identify women at genetically high risk who can be targeted for screening and intervention, and it will allow classification of ovarian cancers into genetic subtypes, thereby facilitating the study of etiologic factors and the planning of strategies for screening and prevention.