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调查导致鉴定出唯一已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因子2A(CDKN2A或p16)(Cannon Albright等人，1992；Cannon Albright等人，1994；Kamb等人)。(1994年)。然而，只有20-40%的黑色素瘤高危家系有p16突变，这表明存在额外的黑色素瘤易感基因。这也得到了所研究的信息性黑色素瘤家系的存在的支持，这些黑色素瘤家系在p16基因的编码区没有突变，也没有表现出与染色体9p21上的p16基因座的连锁。该项目的目标是通过犹他州高危黑色素瘤家系的基因特征确定其他黑色素瘤易感基因，这些黑色素瘤家系似乎不是由p16、ARF或CDK4引起的。 这项研究将利用犹他大学独有的资源来识别非p16黑色素瘤易感基因。这些资源包括1)犹他州人口数据库(UPDB)，该数据库可以识别和招募大量扩展的高危黑色素瘤家系，并促进对用于识别p16的犹他州原始高危家系集合的调查；2)高度集中的家族性黑色素瘤研究诊所(FMRC)，致力于对高危黑色素瘤家系中的高危亲属进行临床检查和分子表征。 我们将识别和采样高危黑色素瘤家系，对没有9P参与迹象的家系进行基因组搜索，并精细绘制任何已确定的易感区域。黑色素瘤易感基因的识别最终将提高我们适当筛查高危患者的能力，并将提出其他可能作为黑色素瘤诊断和治疗靶点的分子途径。

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.