Investigating the association between the somatic and inherited genetics of pheoc

描述（由申请人提供）：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，但由于过量的儿茶酚胺产生导致高血压、中风甚至死亡，仍然具有很高的发病率和死亡率。大约四分之一的PCC/ pgl是恶性的，定义为远处转移。超过三分之一的PCC/PGLs在10个已知易感基因中有一个突变，包括VHL、SDHA、SDHB、SDHC、SDHD、shaf2、NF1、RET、TMEM127和MAX。尽管这种疾病的遗传基因及其基于表达谱和甲基化状态的分组已经得到了很好的描述，但PCC/PGL的体细胞突变和基因组畸变，特别是与遗传突变的关系以及彼此之间的关系却知之甚少。TCGA在罕见肿瘤中的工作将增加我们对PCC/ pgl的体细胞谱的理解。然而，该计划仅包括50种肿瘤，并侧重于恶性和/或SDHB突变阳性的PCC/PGL，这是已知疾病谱系的一个子集。在Specific Aim 1中，我们提出了全外显子组（肿瘤和种系）、低覆盖率（5倍）全基因组测序（肿瘤）和转录组测序（肿瘤中的RNA Seq）的组合，以表征30例恶性肿瘤风险较低的PCC/PGLs，包括VHL突变，以及cmp - l /0组，无论是偶发性（非sdhx /VHL）还是种系MAPK和PI3K途径突变（例如RET/NF1），这将补充TCGA的工作。我们将对80例TCGA和Penn PCC/ pgl进行数据分析，因为我们假设一些体细胞基因突变和基因组畸变在所有PCC/ pgl中是共同的，尽管它们的恶性潜能不同，或者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Specific Aim 2a中，我们将使用125个样本（80个发现，45个验证），确定与临床良性PCC/ pgl相比，不同的体细胞突变和畸变模式是否与临床侵袭性PCC/ pgl相关。我们假设与临床侵袭性疾病相关的PCC/PGL与临床良性疾病相关的PCC/PGL的体细胞突变和畸变模式不同。我们将在Specific Aim 2b中进行探索性分析，以确定具有不同已知遗传突变的PCC/ pgl之间的突变谱是否存在差异。这些研究将使我们能够更好地理解如此广泛的易感基因的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能率差异很大。我们特别感兴趣的是，具有不同已知遗传突变的PCC/PGL是否可能具有不同的突变谱，从而为促进肿瘤发生和恶性转化的机制提供见解，这将与所有肿瘤类型相关。最后，本研究的结果将使我们进一步了解PCC/PGL的肿瘤生物学，并确定PGL/PCL治疗的新靶点，这是迫切需要的。

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.