Redefining the Molecular Landscape of Melanoma

重新定义黑色素瘤的分子景观

• 批准号: 9889799
• 负责人: Jake Conway
• 金额: $ 3.87万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889799
• 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; Immune; Lead; Lesion; MAP Kinase Gene; Malignant Neoplasms; 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; chromatin remodeling; cohort; differential expression; 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： 以前针对黑色素瘤基因组特征的研究导致了四个分类 基于三个最频繁突变的存在的基因组亚型，相互 独有的驱动基因：BRAF、NRAS、NF1和Triple WT(野生型)。三重WT黑色素瘤 这一亚型中最低的突变负担和显著突变的基因(SMGs)尚未确定。 三重WT黑色素瘤的突变谱也显示出突变信号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 过程是导致三重WT黑色素瘤的原因。聚集了更大的黑色素瘤队列，随后是协调 而统一的基因组分析将能够识别SMGs、途径、拷贝数改变 (CNAS)和低频率的突变过程，以及丰富的三重WT黑色素瘤。 这些亚型还表现出不同的临床特征、结果和免疫学特征。因此，更多 这些亚型的详细基因组特征将对识别新的生物靶点至关重要 以及低频驱动基因、通路和突变过程的治疗脆弱性。 黑色素瘤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，主要是 专注于启动子区域的突变。然而，有大量的资源可以研究非编码的本地化 与染色质结构、调控元件和其他表观基因组因子有关的突变和SVS。 因此，聚集更大的黑色素瘤全基因组将阐明非编码谱。 突变和SVS，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，我将汇总1000多个黑色素瘤完整外显子样本 以前发表的研究并执行协调的基因组分析。具体地说，我将确定SMG和 亚型之间和亚型内的转录差异、活跃的突变过程和 CNA反复靶向的染色体区域。另外，我将汇总超过250个黑色素瘤- 从先前发表的研究中提取基因组样本，并进行协调统一的分子分析。 具体地说，我将识别肯定选择的非编码元素、SVS反复靶向的区域，以及 驾驶员融合。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SVS叠加到调控序列和TAD边界上的统计框架 来自Hi-C数据。这项拟议的工作将使人们对分子图景有更全面的了解 黑色素瘤，更精细的亚型，以及对导致三重WT黑色素瘤的变化和机制的洞察。 因此，这些发现可能会促进临床应用，并引发针对新生物学的临床试验。 靶点和治疗的脆弱性。 好了！