Inherited genetic variation and penetrance of Hereditary Paraganglioma-Pheochromocytoma Syndrome

项目总结 目前治疗晚期或转移性嗜铬细胞瘤/副神经节瘤(PGL/PCC)的方法如下 不能治愈，也没有已知的分子或遗传标记来预测原发或转移的外显率 疾病。尽管大多数患者都有散发性肿瘤，但高达40%的患者有遗传因素导致他们的PGL/PCC， 至少识别了12种不同的易感基因。琥珀酸脱氢酶亚单位(SDH)基因 形成线粒体呼吸链的复合体II，参与Kreb循环转化琥珀酸 使之发烟。任何SDHx基因的生殖系致病变异都会增加发生遗传性疾病的风险 PGL/PCC综合征。这种综合征的定义是多灶性原发PGL/PCC，肾细胞 癌症和胃肠道间质瘤。SDHx致病基因携带者的疾病外显性 生殖系变异因基因而异。此外，没有预测原发肿瘤发展的标记物。 或转移性疾病。这种对基因型和表型之间的理解差距使临床 关于筛查和监测的建议很困难，并在实地造成了未得到满足的需求。的目标 这项建议是为了确定发生PGL/PCC的遗传风险基因座，以更好地了解该病的病因。 癌症并确定SDHx相关的PGL/PCC的基因修饰物可直接翻译到临床治疗 用于预测癌症风险和预后，以及确定癌症预防的治疗目标 和治疗。利用国际美国-澳大利亚-亚洲肾上腺联盟(A5)财团，我们 已经组装了已知最大的1740个生殖系DNA样本集，并匹配了来自患者的临床数据 散发性和SDHx相关的PGL/PCC以及生殖系SDHx致病变异体的患者 不含PGL/PCC。在目标1中，我们将确定PGL/PCC的遗传风险基因座，以便更好地了解 通过进行病例对照全基因组SNP分析来研究癌症的遗传病因。在目标2中，我们将 确定SDHx致病变异携带者发生PGL/PCC的遗传风险修饰物 在患有和不患有疾病的SDHx携带者之间进行病例对照研究。目标3专注于稀有变种 其可能是SDHB相关的PGL/PCC的修饰物。SDHB携带者最多 罹患转移性疾病的风险。最后，利用eQTL分析和调控等多种方法 元素分析，我们将确定最有可能的因果变异来测试体外功能分析。成功 确定散发性或SDHx相关的PGL/PCC的遗传修饰物将直接转化为临床 通过确定个性化筛查方法的最高风险人群和确定癌症靶点进行护理 预防和治疗干预。

PROJECT SUMMARY Current therapies for patients with advanced or metastatic pheochromocytoma/paraganglioma (PGL/PCC) are not curative and there are no known molecular or genetic markers to predict penetrance of primary or metastatic disease. Although most patients have sporadic tumors, up to 40% have a hereditary cause for their PGL/PCC, with at least 12 different susceptibility genes identified. The Succinate Dehydrogenase Subunit (SDH) genes form complex II of the mitochondrial respiratory chain and are involved with the Kreb’s cycle converting succinate to fumarate. Germline pathogenic variants in any of the SDHx genes increases risk of developing Hereditary PGL/PCC Syndrome. This syndrome is defined by the development of multifocal primary PGL/PCC, renal cell carcinoma and gastrointestinal stromal tumors. The penetrance for the disease in carriers of SDHx pathogenic germline variants varies per gene. Furthermore, there are no predictive markers for primary tumor development or metastatic disease. This gap in understanding between genotype and phenotype makes clinical recommendations for screening and surveillance difficult and creates an unmet need in the field. The goals of this proposal are to identify genetic risk loci for developing PGL/PCC to better understand the etiology of the cancer and to identify genetic modifiers for SDHx-associated PGL/PCC to be directly translatable to clinical care for prediction of cancer risk and prognosis as well as identification of therapeutic targets for cancer prevention and treatment. Leveraging the international American-Australian-Asian Adrenal Alliance (A5) consortium, we have assembled the largest known sample set of 1740 germline DNAs and matched clinical data from patients with sporadic and SDHx-associated PGL/PCC as well as patients with germline SDHx pathogenic variants without PGL/PCC. In Aim 1, we will determine the inherited genetic risk loci for PGL/PCC to better understand the genetic etiology of the cancer by performing a case control genome-wide SNP analysis. In Aim 2, we will determine inherited genetic risk modifiers for SDHx pathogenic variant carriers to develop PGL/PCC by performing a case-control study between SDHx carriers with and without disease. Aim 3 focuses on rare variants within the SDH complex which may be modifiers for SDHB-associated PGL/PCC. SDHB carriers are at highest risk for developing metastatic disease. Finally, using several methods including eQTL analysis and regulatory element analysis, we will identify the most likely causal variants to test with in vitro functional assays. Successful identification of genetic modifiers for sporadic or SDHx-associated PGL/PCC will have direct translation to clinical care by identifying those at highest risk for a personalized screening approach and identifying targets for cancer prevention and therapeutic intervention.