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）对当前治疗具有高度耐药性。我们假设转移性UM细胞的前体在原发肿瘤中以小水平存在。携带突变细胞的水平与肿瘤异质性有关，这意味着存在多个具有不同突变谱的克隆。随着时间的推移，这些细胞随着治疗和各种宿主因素的作用而进化。我们将使用下一代测序的方法，对多个肿瘤基因组的整个外显子组和癌症外显子组进行无偏观察。第一个目标是定义转移性UM的体细胞突变谱，并比较匹配的原发和转移性病变的谱，以确定哪些突变在转移性病变中被选择。此外，确定已知癌症相关基因的突变，这些突变可能在原发肿瘤中以非常高（常见）或低（罕见）的水平存在，在转移性肿瘤中也有选择。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部分的突变特征。这将检测不同频率的突变，如果存在，在切片和定义肿瘤内的异质性。第三个目的是比较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志物。临床相关性可以是一个大肿瘤的一次活组织检查不能提供足够的关于突变阵列的信息来设计临床试验或基于肿瘤遗传谱的治疗。此外，该结果可能会导致新的治疗靶点在UM。

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.