Dissecting the Melanoma Genome

剖析黑色素瘤基因组

基本信息

批准号：
8435369
负责人：
Julide T. Celebi
金额：
$ 6.4万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-29 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435369
关键词：
Affect Amino Acids Anchorage-Independent Growth Apoptosis BRAF gene Biological Assay CDKN2A gene Cancer Biology Candidate Disease Gene Chromosomes Classification Clinical Code DNA Data Development Diagnosis Disease Event Frequencies Future GAB2 gene Gene Expression Profile Genes Genetic Genome Genome Mappings Genomic Hybridizations Genomics Germ Lines Goals Growth Hereditary Disease Human Knowledge Lead Link Location Malignant Neoplasms Maps Metastatic Melanoma Methods Molecular Diagnosis Molecular Genetics Mutate Mutation Neoplasm Metastasis Nucleotides Oncogenes Oncogenic Outcome Patients Peripheral Blood Lymphocyte Point Mutation Prognostic Marker Proto-Oncogene Proteins c-akt Recurrence Resolution Role Sampling Signal Transduction Somatic Mutation Specimen Structure Technology Testing Translating Tumor Suppressor Genes Tumor Suppressor Proteins Tumorigenicity Work base cancer cell cancer genome cancer genomics clinical decision-making clinically significant comparative genomic hybridization effective therapy exome exome sequencing gain of function mutation genome sequencing genome-wide in vivo insertion/deletion mutation insight melanoma migration molecular marker next generation sequencing novel therapeutic target tool tumor tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：转移性黑色素瘤是一种侵略性恶性肿瘤，缺乏可预测患者预后和有效疗法的分子标记物。黑色素瘤的分子遗传学尚未充分表征。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。在我们先前的研究中，我们通过全基因组BAC阵列比较基因组杂交分析分析转移性黑色素瘤样品的复发性狭窄扩增和缺失。我们的拷贝数数据表明存在具有先前未定义的遗传事件的染色体区域。值得注意的是，我们最近将Acral黑色素瘤子集中的GAB2扩增描述为一种新的遗传事件，并通过激活PI3K-AKT信号传导来证明其在黑色素瘤转移中的关键作用。根据我们以前的工作，我们现在将进行研究，以表征新颖的癌基因和抑制肿瘤基因对黑色素瘤转移至关重要的基因。我们将使用遗传，生物学和临床方法的组合来追求两个链接的特定目标。（1）通过整个外显子组测序方法定义和验证在转移性黑色素瘤中突变的候选基因，在放大和缺失中绘制突变基因，并选择候选物。（2）突变分析和功能测定将表征候选基因，并探索黑色素瘤中的致癌和肿瘤抑制功能。该提案中的研究通过利用包括高吞吐量的下一代测序（旨在鉴定具有潜在高临床意义的新型肿瘤基因或肿瘤抑制基因），包括当前和未来的分子诊断和结果预测研究的研究，扩大了我们对黑色素瘤分子遗传学的了解。该提案中的研究旨在将获得的知识从分子遗传学转化为可用于临床决策的工具。