BASAL CELL CARCINOMAS--CLONING OF A TUMOR SUPRESSOR GENE

此应用程序请求支持4-8年的项目，其目标是 是识别基因，其功能的丧失在以下方面很重要： 基底细胞癌（BCC）的发展，迄今为止最常见的 人类癌症 在视网膜母细胞瘤范例中，有一种形式的 基底细胞癌，与散发型相比， 肿瘤发生在年轻的时候，在更大的数量，并与常染色体 显性遗传-基底细胞痣综合征（BCNS）。 在过去的几年中，我们评估了BCNS表型的连锁 在全基因组搜索中， 基因的位置。 最近，其他研究人员发现， 连锁在染色体9 q，一个网站，我们随后证实，在我们的 我们现在建议更充分地描述等位基因丢失， 在BCC中的这个位点，并通过“位置突变”来寻找BCNS基因本身。 克隆”策略，这在很大程度上依赖于重新排列的搜索 破坏BCC中的基因，或者优选地，破坏“组成”DNA中的基因， BCNS患者。 这项工作的成功完成不仅应导致基本的 深入了解皮肤癌的发生， 肿瘤与多表型异常的关系 遗传综合症。

This application requests support for years 4-8 of a project whose goal is the identification of genes the loss of whose function is important in the development of basal cell carcinomas (BCCs), by far the most common human cancer. As in the retinoblastoma paradigm, there is a form of basal cell carcinoma in which, by comparison with the sporadic type, tumors arise at younger age, in greater numbers, and with autosomal dominant inheritance- the basal cell nevus syndrome (BCNS). During the past several years, we assessed linkage of the BCNS phenotype to more than 120 sites in a genome-wide search without identifying the location of the gene. Very recently, other investigators found such linkage at chromosome 9q, a site that we subsequently confirmed in our own kindreds We propose now to characterize more fully allelic loss at this site in BCCs and to search for the BCNS gene itself by a "positional cloning" strategy that relies heavily on a search for rearrangements disrupting the gene in BCCs or, preferably, in "constitutional" DNA from BCNS patients. Successful completion of this work should lead not only to fundamental insights into cutaneous carcinogenesis but also to understanding of the relationship of the tumors to the multiple phenotypic abnormalities of the inherited syndrome.