Investigating the association between the somatic and inherited genetics of pheoc

描述(申请人提供)：嗜铬细胞瘤和副神经节瘤(PCC/PGL)分别是肾上腺髓质或肾上腺外神经节的肿瘤。大多数是良性的，但由于儿茶酚胺的过度产生导致高血压、中风甚至死亡，其发病率和死亡率仍然很高。根据远处转移的定义，大约四分之一的PCC/PGL是恶性的。超过三分之一的PCC/PGL在VHL、SDHA、SDHB、SDHC、SDHD、SDHAF2、NF1、RET、TMEM127和MAX等十个已知易感基因中的一个存在突变。虽然这种疾病的遗传遗传学及其基于表达谱和甲基化状态的分组得到了很好的描述，但PCC/PGL的体细胞突变和基因组异常，特别是与遗传突变的关系和相互之间的关系，却知之甚少。TCGA在罕见肿瘤中的努力将增加我们对PCC/PGLS体型的了解。然而，这些计划只包括50个肿瘤，并专注于恶性肿瘤和/或SDHB突变阳性的PCC/PGL，这是已知疾病谱的一个子集。在具体目标1中，我们建议结合全外显子组(在肿瘤和胚系中)、低覆盖率(5x)全基因组测序(在肿瘤中)和转录组测序(在肿瘤中)来表征30个恶性风险较低的PCC/PGL，包括VHL突变，以及CIMP-L/0组，要么是零星的(非SDHx/VHL)，要么是带有种系MAPK和PI3K途径突变的(例如RET/NF1)，这将补充TCGA的努力。数据分析将对80例TCGA和宾夕法尼亚大学PCC/PGL的组合进行，因为我们假设一些体细胞基因突变和基因组异常将是所有PCC/PGL的共同之处，尽管它们具有不同的恶性潜能，或发生在交叉遗传突变状态的子集中。我们将在115个独立的PCC/PGL中验证我们的发现。在特定的目标2a中，我们将使用125个样本(80个发现，45个验证)来确定与临床良性PCC/PGL相比，不同的体细胞突变和异常模式是否与临床侵袭性PCC/PGL相关。我们假设，在与临床侵袭性疾病和临床良性疾病相关的PCC/PGL中，体细胞突变和异常的模式将不同。我们将针对特定的目标2b进行探索性分析，以确定具有不同已知遗传突变的PCC/PGL之间的突变谱是否不同。这些研究将使我们能够更好地理解如此广泛的易感基因突变如何导致相同的肿瘤类型，以及为什么遗传突变组之间的恶性潜在率差异很大。我们特别感兴趣的是，具有不同已知遗传突变的PCC/PGL是否具有不同的突变谱，从而深入了解促进肿瘤发生和恶变的机制，这将与所有肿瘤类型相关。最后，这项研究的结果将使我们能够大大加深我们对PCC/PGL肿瘤生物学的理解，并确定迫切需要的PGL/PCL治疗的新靶点。

DESCRIPTION (provided by applicant): Pheochromocytomas and paragangliomas (PCC/PGL) are tumors of the adrenal medulla or extra-adrenal ganglia, respectively. Most are benign yet still carry high morbidity and mortality due to excessive catecholamine production leading to hypertension, stroke and even death. Approximately one-fourth of PCC/PGLs are malignant, defined by distant metastases. Over one-third of PCC/PGLs have a mutation in one of ten known susceptibility genes, including VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, RET, TMEM127 and MAX. Whereas the inherited genetics of this disease and their grouping based on expression profiling and methylation status are well described, somatic mutations and genomic aberrations in PCC/PGL, in particular in relationship to inherited mutations and each other are very poorly understood. The TCGA effort in rare tumors will increase our understanding of the somatic profiles of PCC/PGLs. However, the plans include only 50 tumors, and focus on malignant and/or SDHB mutation positive PCC/PGL, a subset of the known disease spectrum. In Specific Aim 1, we propose a combination of whole exome (in tumor and germline), low coverage (5x) whole genome sequencing (in tumor) and transcriptome sequencing (RNA Seq in tumor) to characterize 30 PCC/PGLs with a lower risk of malignancy, including VHL mutated, and the CIMP-L/0 group, either sporadic (non-SDHx/VHL) or with germline MAPK and PI3K pathway mutations (e.g. RET/NF1), which will complement the TCGA effort. Data analysis will be done across the combined set of 80 TCGA and Penn PCC/PGLs, as we hypothesize that some somatic genetic mutations and genomic aberrations will be common to all PCC/PGLs, despite their differing malignant potential, or occur in sub-sets crossing inherited mutational status. We will validate our findings in 115 independent PCC/PGLs. In Specific Aim 2a, we will determine if distinct patterns of somatic mutations and aberrations are associated with clinically aggressive PCC/PGLs compared to clinically benign PCC/PGLs using 125 samples (80 discoveries, 45 validations). We hypothesize that the pattern of somatic mutations and aberrations will differ in PCC/PGL associated with clinically aggressive disease from clinically benign disease. We will perform an exploratory analysis in Specific Aim 2b to determine if the mutational spectrum differs between PCC/PGLs with different known inherited mutations. These studies will enable us to better understand how mutations in such a broad range of susceptibility genes can lead to the same tumor type, and why the rates of malignant potential vary greatly between inherited mutation groups. We are particularly interested in whether PCC/PGL with different known inherited mutations may have distinct mutational spectra providing insights into the mechanisms promoting tumorigenesis and malignant transformation, which would be relevant for all tumor types. Finally, the results of thi study will allow us to substantially further our understanding of the tumor biology of PCC/PGLs, and identify novel targets for therapeutics for PGL/PCL, which are critically needed.