Identification of a Melonoma Susceptibilty Gene at 1p22

描述（由申请人提供）：皮肤恶性黑色素瘤（CMM）的发病率正在上升，约占美国癌症诊断的4%。最近，在1号染色体（1p22）上发现了一个新的CMM易感位点。为了鉴定该基因Aim 1，我们将采用多学科方法对关键区域内的基因进行综合鉴定、优先排序和筛选。我们将构建一个定制的寡核苷酸微阵列，用探针代表所有进化上保守的1p22序列，并在黑色素细胞和黑色素瘤细胞系中检测表达，以鉴定该区域的所有表达基因。我们将使用这些CGH阵列来筛选家族性CMM患者和散发性黑色素瘤细胞系的缺失。我们将对我们的家族进行snp基因型，并进行基于连锁不平衡的关联研究，以缩小1p22的关键区域。基于这些实验，我们将优先考虑1p22候选基因进行高通量突变筛选。一旦确定了CMM易感基因，我们将寻找基因型-基因型相关性，验证低外显率遗传CMM危险因素作为1p22突变外显率修饰因子的假设（目的2）。最后，我们将确定1p22突变在散发性黑色素瘤细胞系和肿瘤中的患病率（目的3）。

DESCRIPTION (provided by applicant): Cutaneous malignant melanoma (CMM) incidence is rising, accounting for approximately 4% of cancer diagnoses in U.S. Recently, a novel CMM susceptibility locus was identified on chromosome 1 (1p22). To identify this gene Aim 1, we will use a multidisciplinary approach to comprehensively identify, prioritize, and screen genes within the critical region. We will construct a custom oligonucleotide microarray with probes representing all evolutionarily conserved sequence at 1p22 and assay expression in melanocytes and melanoma cell lines to identify all expressed genes in the region. We will use these arrays for CGH to screen for deletions in familial CMM patients and sporadic melanoma cell lines. We will SNP-genotype our families and perform a linkage disequilibrium based association study to narrow the 1p22 critical region. Based on these experiments, we will prioritize 1p22 candidates for high-throughput mutation screening. Once the CMM susceptibility gene is identified, we will look for genotype-genotype correlation, testing the hypothesis that Iow-penetrance genetic CMM risk factors act as modifiers to the penetrance of 1p22 mutations (Aim 2). Finally, we will determine the prevalence of 1p22 mutations in sporadic melanoma cell lines and tumors (Aim 3).