Mutation Profile as Translatable Prognostic Biomarker of Uveal Melanoma

描述(由申请人提供)：葡萄膜黑色素瘤(UM)对目前的治疗方法高度耐药。我们假设转移的UM细胞的前体在原发肿瘤中存在于很小的水平。携带突变细胞的水平与肿瘤的异质性有关，这意味着存在具有不同突变谱的多个克隆。随着治疗和各种宿主因素的作用，这些细胞会随着时间的推移而演变。我们将使用下一代测序的方法来公正地研究整个外显子组，然后是多个肿瘤基因组的癌症外显子组。第一个目标是定义转移性UM的体细胞突变谱，并比较匹配的原发灶和转移灶的谱，看看在转移灶中选择了哪些突变。此外，在原发肿瘤和转移性UM中识别已知癌症相关基因的突变，这些突变可能存在于非常高(常见)或低水平(罕见)。第二个目标是比较基于大小和细胞类型特征选择的同一肿瘤的不同切片的突变特征。这将在切片中检测到不同频率的突变，并确定肿瘤内的异质性。第三个目标是将已确定的肿瘤内异质性与其他已知的肿瘤遗传、临床和组织学特征作为预后标记物进行比较。临床相关性可以是这样的知识，即一个大肿瘤的一次活组织检查不能提供关于存在的突变阵列的足够信息，以基于肿瘤的基因图谱来设计临床试验或治疗。此外，这一结果可能会导致UM的新治疗靶点。

DESCRIPTION (provided by applicant): Uveal melanoma (UM) is highly resistant to current therapies. We hypothesize that precursors of metastatic UM cells are present at a small level in the primary tumor. The level of the mutation bearing cells is related to tumor heterogeneity implying the presence of multiple clones with different mutation spectrums. These cells evolve over time as a function of therapy and a variety of host factors. We will use the methods of next generation sequencing to take an unbiased look at the whole exome followed by cancer exome of multiple tumor genomes. The first objective is to define the somatic mutation profile of metastatic UM and compare the profiles of matched primary and metastatic lesions to see which mutations are selected in the metastatic lesions. In addition, identify mutations in known cancer associated genes, which may be present at very high (common) or low levels (rare), in the primary tumor and selected in metastatic UM. The second objective is to compare the mutation profiles of different sections of the same tumors selected based on the size and cell type profiles. This will detect different frequencies of mutations, if present, in the sections and defie intra-tumor heterogeneity. The third objective is to compare identified intra-tumor heterogeneity to other known genetic, clinical and histological features of the tumor as prognostic markers. The clinical relevance can be the knowledge that one biopsy of a large tumor does not provide enough information about the array of mutations present to design clinical trials or treatments based on the genetic profile of the tumor. In addition, the results may lead to novel therapeutic targets in UM.