BASAL CELL CARCINOMAS--CLONING OF A TUMOR SUPRESSOR GENE

此应用程序请求对项目的第4-8年提供支持，该项目的目标是 对功能丧失的基因的鉴定在 发生基底细胞癌(BCC)是目前为止最常见的 人类癌症。在视网膜母细胞瘤的范例中，有一种形式的 基底细胞癌，与散发性相比， 肿瘤发生的年龄更小，数量更多，而且常染色体 显性遗传-基底细胞痣综合征(BCNS)。 在过去的几年里，我们评估了BCNS表型的连锁 在全基因组搜索中搜索到超过120个位置，但没有识别 基因的位置。就在最近，其他调查人员发现 染色体9q上的连锁，我们随后在我们的 我们现在建议更全面地描述等位基因丢失的特征 在BCCS中的这个位置，并搜索BCNS基因本身的一个位置 在很大程度上依赖于对重组的搜索的“克隆”战略 扰乱BCC中的基因，或者最好是扰乱来自 BCNS患者。 这项工作的成功完成不仅应该导致根本 对皮肤癌发生的洞察，也是对 肿瘤与多种表型异常的关系 遗传性综合症。

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.