Dissecting the Melanoma Genome

描述（由申请人提供）：转移性黑色素瘤是一种侵袭性恶性肿瘤，缺乏可预测患者结局的分子标志物以及有效治疗。黑色素瘤的分子遗传学特征尚未完全确定。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。在我们以前的研究中，我们通过全基因组BAC阵列比较基因组杂交分析转移性黑色素瘤样本，确定了复发性窄扩增和缺失。我们的拷贝数数据表明存在先前未定义的遗传事件的染色体区域。值得注意的是，我们最近描述了GAB 2扩增在肢端黑色素瘤的一个子集作为一种新的遗传事件，并证明了其在黑色素瘤转移通过激活PI 3 K-AKT信号的关键作用。基于我们以前的工作，我们现在将继续研究黑色素瘤转移关键的新癌基因和肿瘤抑制基因。我们将采用遗传学、生物学和临床方法相结合的方法，追求两个相互联系的具体目标。(1)通过全外显子组测序的方法确定和验证转移性黑色素瘤中突变的候选基因，定位扩增和缺失中的突变基因，并选择候选基因。(2)突变分析和功能测定将描述候选基因的特征，并探索黑色素瘤的致癌和肿瘤抑制功能。本提案中的研究通过利用最先进的技术（包括高通量下一代测序）扩展了我们对黑色素瘤分子遗传学的了解，旨在鉴定具有潜在高临床意义的新癌基因或抑癌基因，并包括目前和未来的分子诊断和结局预测研究。该提案中的研究旨在将从分子遗传学中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.