Redefining the Molecular Landscape of Melanoma

重新定义黑色素瘤的分子景观

• 批准号: 10133450
• 负责人: Jake Conway
• 金额: $ 2.31万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133450
• 关键词: Algorithms; Architecture; Automobile Driving; BRAF gene; Binding Sites; Biological; Characteristics; Chromatin; Classification; Clinical; Clinical Trials; Computational algorithm; Computing Methodologies; DNA Sequence Alteration; Data; Elements; Epigenetic Process; Event; Frequencies; Genes; Genome; Genomics; Hi-C; Immune; Lead; MAP Kinase Gene; Malignant neoplasm of prostate; Molecular; Molecular Analysis; Mutate; Mutation; Mutation Spectra; NF1 gene; Oncogenic; Outcome; Pathway interactions; Process; Promoter Regions; Publishing; Recurrence; Regulatory Element; Reporting; Research; Resources; Role; Running; Sample Size; Sampling; Structure; The Cancer Genome Atlas; Tumor-infiltrating immune cells; UV Mutagenesis; UV induced; Untranslated RNA; Variant; Work; base; cancer type; chromatin remodeling; cohort; differential expression; driver mutation; epigenome; epigenomics; exome; experience; insight; melanocyte; melanoma; new therapeutic target; novel; programs; promoter; targeted treatment; therapeutic target; transcription factor; treatment response; tumor; whole genome

Project Abstract: Previous studies aimed at the genomic characterization of melanoma led to the classification of four genomic subtypes based on the presence of mutations in the three most frequently mutated, mutually exclusive, driver genes: BRAF, NRAS, NF1 and Triple WT (wild-type). Triple WT melanomas experience the lowest mutational burden, and significantly mutated genes (SMGs) in this subtype have yet to be identified. The mutational spectra of Triple WT melanomas also display low contributions of mutational signature 7 (UV mutagenesis), which is in stark contrast to the other melanoma subtypes, suggesting that other mutational processes are driving Triple WT melanomas. Aggregation of a larger melanoma cohort followed by harmonized and uniform genomic analysis would enable the identification of SMGs, pathways, copy-number alterations (CNAs) and mutational processes implicated at lower frequencies, as well as enrich for Triple WT melanomas. These subtypes also display diverse clinical characteristics, outcomes and immune profiles. Thus, more detailed genomic characterization of these subtypes will be paramount to identifying novel biological targets and therapeutic vulnerabilities of low frequency driver genes, pathways, and mutational processes. The spectrum of noncoding mutations and structural variants (SV) in melanoma remains largely undefined. Previous studies have considered transcription factor binding sites as a single entity, and primarily focused on mutations in promoter regions. However, vast resources exist to study the localization of noncoding mutations and SVs with respect to chromatin architecture, regulatory elements and other epigenomic factors. Thus, aggregation of a larger cohort of melanoma whole-genomes would elucidate the spectrum of noncoding mutations and SVs, and their interplay with melanocyte chromatin architecture and regulatory mechanisms. In this proposed research, I will aggregate upwards of 1000 melanoma whole-exome samples from previously published studies and perform harmonized genomic analysis. Specifically, I will identify SMGs both across and within subtypes, transcriptional differences between the subtypes, active mutational processes, and chromosomal regions recurrently targeted by CNAs. Additionally, I will aggregate over 250 melanoma whole- genome samples from previously published studies, and perform harmonized and uniform molecular analysis. Specifically, I will identify positively selected noncoding elements, regions recurrently targeted by SVs, and driver fusions. Additionally, to define the functional relevance of noncoding events, I will develop a Bayesian statistical framework that superimposes mutations and SVs onto regulatory sequences and TAD boundaries from Hi-C data. The proposed work will yield a more comprehensive insight into the molecular landscape of melanoma, more refined subtypes, and insight into alterations and mechanisms driving Triple WT melanomas. As such, these findings may prompt clinical implications and provoke clinical trials aimed at novel biological targets and therapeutic vulnerabilities. !

项目摘要： 先前针对黑色素瘤基因组特征的研究导致了四种黑色素瘤的分类， 基因组亚型基于三个最频繁突变的基因组中存在的突变， 排他性驱动基因：BRAF、NRAS、NF 1和三重WT（野生型）。三重WT黑色素瘤经历 最低的突变负担，并且该亚型中的显著突变基因（SMG）尚未被鉴定。 三重WT黑色素瘤的突变谱也显示突变标记7（UV）的低贡献 突变），这与其他黑色素瘤亚型形成鲜明对比，表明其他突变 三重WT黑色素瘤的发病机制更大黑色素瘤队列的聚合，随后进行协调 统一的基因组分析将能够识别SMG，途径，拷贝数改变， （CNA）和涉及较低频率的突变过程，以及富集三重WT黑色素瘤。 这些亚型还显示出不同的临床特征、结局和免疫特征。因此更 这些亚型的详细基因组特征对于鉴定新的生物靶点是至关重要的 以及低频驱动基因、途径和突变过程的治疗弱点。 黑色素瘤中的非编码突变和结构变异（SV）谱在很大程度上仍然存在 未定义。以前的研究认为转录因子结合位点是一个单一的实体， 集中于启动子区域的突变。然而，存在大量的资源来研究非编码的本地化 关于染色质结构、调控元件和其他表观基因组因子的突变和SV。 因此，更大的黑色素瘤全基因组群体的聚集将阐明黑色素瘤非编码基因的谱。 突变和SV，以及它们与黑素细胞染色质结构和调节机制的相互作用。 在这项拟议的研究中，我将收集1000多个黑色素瘤全外显子组样本， 以前发表的研究，并进行协调的基因组分析。具体来说，我将确定SMG和 亚型之间和亚型内的转录差异，活跃的突变过程，以及 CNA反复靶向的染色体区域。另外，我会收集超过250个黑色素瘤- 基因组样本从以前发表的研究，并进行协调和统一的分子分析。 具体来说，我将确定积极选择的非编码元件，区域反复靶向SV， 驱动程序融合。此外，为了定义非编码事件的功能相关性，我将开发一个贝叶斯 将突变和SV叠加到调控序列和边界上的统计框架 Hi-C数据拟议的工作将产生一个更全面的洞察分子景观 黑色素瘤，更精细的亚型，以及对驱动三重WT黑色素瘤的改变和机制的洞察。 因此，这些发现可能会引发临床影响，并引发针对新型生物学的临床试验 目标和治疗弱点。 !