IDENTIFICATION OF MELANOMA PREDISPOSITION LOCI

描述（由申请人提供）：先前对犹他州黑色素瘤家系的研究导致鉴定了唯一尚未鉴定的主要黑色素瘤易感基因，细胞周期蛋白依赖性激酶抑制剂2A（CDKN 2A或p16）（Cannon Albright et al.，1992; Cannon Albright等人，1994; Kamb et al.1994）。然而，只有20-40%的黑色素瘤高危家系有p16突变，这表明存在其他黑色素瘤易感基因。这也得到了研究的信息性黑色素瘤家系的存在的支持，这些家系在p16基因的编码区没有突变，也没有证明与染色体9 p21上的p16基因座的连锁。本项目的目的是通过犹他州高风险黑色素瘤家系的基因型特征来鉴定其他黑色素瘤易感基因，这些家系似乎不是由于p16、ARF或CDK 4引起的。 这项研究将利用犹他州大学独有的资源来鉴定非p16黑色素瘤易感基因。这些资源包括：1）犹他州人口数据库（UTB），该数据库允许识别和招募大量，扩展了高危黑色素瘤家系，并促进了对用于鉴定p16的原始犹他州高危家系收集的调查，以及2）高度集中的家族性黑色素瘤研究诊所（FMRC），致力于高危黑色素瘤患者的临床检查和高危亲属的分子表征，风险黑色素瘤家系。 我们将确定和采样高风险黑色素瘤家系，对没有9 p参与迹象的家系进行基因组搜索，并对确定的任何易感区域进行精细定位。黑色素瘤易感基因的鉴定将最终提高我们适当筛查高风险患者的能力，并将提示可能作为黑色素瘤诊断和治疗靶点的其他分子途径。

DESCRIPTION (provided by applicant): Previous investigation of Utah melanoma pedigrees resulted in the identification of the only major melanoma predisposition gene yet identified, cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) (Cannon Albright et al., 1992; Cannon Albright et al., 1994; Kamb et al. 1994). However, only 20-40% of melanoma high-risk pedigrees have a p16 mutation, suggesting that additional melanoma predisposition genes exist. This is also supported by the existence of studied informative melanoma pedigrees that do not have mutations in the coding region of the p16 gene nor demonstrate linkage to the p16 locus on chromosome 9p21. The goal of this project is to identify additional melanoma predisposition genes through the genotypic characterization of Utah high-risk melanoma pedigrees which do not appear to be due to p16, ARF, or CDK4. This investigation will utilize resources that are unique to the University of Utah to identify non-p16 melanoma predisposition genes. These resources include 1) the Utah Population Database (UPDB), which permits identification and recruitment of numerous, extended high-risk melanoma pedigrees and facilitated investigation of the original Utah high-risk pedigree collection used to identify p16 and 2) a highly focused Familial Melanoma Research Clinic (FMRC) that is devoted to the clinical examination and molecular characterization of at-risk relatives in high-risk melanoma pedigrees. We will identify and sample high-risk melanoma pedigrees, perform a genomic search on the pedigrees with no indication of 9p involvement, and fine map any predisposition regions identified. Identification of melanoma predisposition genes will ultimately increase our ability to appropriately screen high-risk patients, and will suggest additional molecular pathways that may serve as targets for the diagnosis and treatment of melanoma.