Dissecting the Melanoma Genome

描述(申请人提供)：转移性黑色素瘤是一种侵袭性的恶性肿瘤，缺乏预测患者预后的分子标志物以及有效的治疗方法。黑色素瘤的分子遗传学尚未完全确定。高分辨率基因组杂交和高通量测序方法的最新进展为进一步表征癌症基因组提供了机会。在我们之前的研究中，我们通过对转移性黑色素瘤样本进行全基因组BAC阵列比较基因组杂交分析来确定复发的狭窄扩增和缺失。我们的拷贝数数据表明，存在具有以前未定义的遗传事件的染色体区域。值得注意的是，我们最近将肢端黑色素瘤的GAB2扩增描述为一种新的遗传事件，并证明了它通过激活PI3K-AKT信号在黑色素瘤转移中的关键作用。在我们以前工作的基础上，我们现在将继续研究新的癌基因和肿瘤抑制基因对黑色素瘤转移至关重要。我们将结合使用遗传学、生物学和临床方法，追求两个相互关联的具体目标。(1)用外显子全测序方法确定和验证转移性黑色素瘤突变候选基因，定位突变基因的扩增和缺失区域，筛选候选基因。(2)突变图谱和功能分析将确定候选基因的特征，并探索黑色素瘤的致癌和抑瘤功能。这项建议中的研究利用最先进的技术，包括高通量下一代测序，扩大了我们对黑色素瘤分子遗传学的了解，旨在发现具有潜在高临床意义的新的癌基因或肿瘤抑制基因，并包括分子诊断和结果预测的现有和未来研究。这项建议中的研究旨在将从分子遗传学获得的知识转化为可用于临床决策的工具。

DESCRIPTION (provided by applicant): Metastatic melanoma is an aggressive malignancy lacking molecular markers predictive of patient outcome as well as effective therapies. The molecular genetics of melanoma has not been fully characterized. Recent advances in high-resolution genomic hybridization and high throughput sequencing methods provide opportunities for further characterization of the cancer genome. In our previous studies, we identified recurrent narrow amplifications and deletions by genome-wide BAC array comparative genomic hybridization analysis of metastatic melanoma samples. Our copy number data suggested the presence of chromosomal regions with previously undefined genetic events. Notably, we recently described GAB2 amplifications in a subset of acral melanomas as a novel genetic event, and demonstrated its critical role in melanoma metastasis via activation of the PI3K-AKT signaling. Based on our previous work, we will now pursue studies to characterize novel oncogenes and tumor suppressor genes critical for melanoma metastasis. We will pursue two linked specific aims, using a combination of genetic, biologic, and clinical approaches. (1) Defining and validating candidate genes mutated in metastatic melanoma by whole exome sequencing approach, mapping the mutated genes within amplifications and deletions, and selecting candidates. (2) Mutational profiling and functional assays will characterize the candidate gene and explore oncogenic and tumor suppressive function in melanoma. The studies in this proposal expand our knowledge on molecular genetics of melanoma by utilizing state-of- the-art technology including high throughput next generation sequencing, aim to identify novel oncogenes or tumor suppressor genes of potential high clinical significance, and include present and future studies for molecular diagnosis and outcome prediction. The studies in this proposal aim to translate knowledge gained from molecular genetics into tools that can be used in clinical decision-making.