Inherited genetic variation and penetrance of Hereditary Paraganglioma-Pheochromocytoma Syndrome

项目摘要 目前晚期或转移性嗜铬细胞瘤/副神经节瘤（PGL/PCC）患者的治疗方法是 没有治愈性的，并且没有已知的分子或遗传标记来预测原发性或转移性癌的复发率。 疾病虽然大多数患者患有散发性肿瘤，但高达40%的PGL/PCC具有遗传原因， 至少有12种不同的易感基因被鉴定出来。琥珀酸脱氢酶亚基（SDH）基因 形成线粒体呼吸链的复合物II，并参与转化琥珀酸的克雷布循环 变成富马酸盐。任何SDHx基因中的生殖系致病性变体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性PGL/PCC，肾细胞浸润， 癌和胃肠道间质瘤。SDHX致病性携带者的发病率 生殖系变异因基因而异。此外，没有原发性肿瘤发展的预测标志物， 或转移性疾病。基因型和表型之间的理解差距使得临床 筛查和监测的建议很困难，在实地造成了未得到满足的需求。的目标 该建议旨在确定发生PGL/PCC的遗传风险位点，以更好地了解PGL/PCC的病因。 癌症，并确定SDHX相关PGL/PCC的遗传修饰剂，以直接转化为临床护理 用于预测癌症风险和预后以及鉴定癌症预防的治疗靶点 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 我收集了已知最大的1740个生殖系DNA样本集，并匹配了患者的临床数据 散发性和SDHx相关PGL/PCC以及具有生殖系SDHx致病性变异的患者 没有PGL/PCC。在目标1中，我们将确定PGL/PCC的遗传风险位点，以更好地了解 通过进行病例对照全基因组SNP分析来确定癌症的遗传病因。在目标2中，我们 确定SDHx致病性变体携带者的遗传遗传风险调节因子，以发展PGL/PCC， 在有病和无病的SDHx携带者之间进行病例对照研究。Aim 3关注罕见变异 在SDH复合物中，其可以是SDHB相关的PGL/PCC的改性剂。SDHB携带者最高 发生转移性疾病的风险。最后，利用eQTL分析和调控分析等方法， 元素分析，我们将确定最有可能的因果变异体测试与体外功能测定。成功 散发性或SDHX相关PGL/PCC的遗传修饰物的鉴定将直接转化为临床应用， 通过识别个性化筛查方法的最高风险人群和识别癌症靶点来进行护理 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.