Inherited genetic variation and penetrance of Hereditary Paraganglioma-Pheochromocytoma Syndrome

遗传性副神经节瘤-嗜铬细胞瘤综合征的遗传变异和外显率

• 批准号: 10228614
• 负责人: Lauren Michelle Fishbein
• 金额: $ 35.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-04 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10228614
• 关键词: Adrenal Glands; Age of Onset; American; Asians; Biological; Biological Assay; Blood; Cancer Etiology; Cancer Prevention Intervention; Cancer Prognosis; Cardiovascular system; Caring; Case-Control Studies; Catecholamines; Clinical; Clinical Data; Colorado; Complex; DNA; DNA Repair; Detection; Development; Disease; Division of Cancer Control and Population Sciences; Emotional; Etiology; Financial Hardship; Fumarates; Gastrointestinal Stromal Tumors; Gene-Modified; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genotype; Glioblastoma; Goals; Hereditary Paraganglioma; Hypoxia; Image; In Vitro; Individual; Inherited; International; Laboratories; Lead; Life; Malignant Neoplasms; Metabolic; Metastatic Pheochromocytoma; Methods; Mitochondria; Morbidity - disease rate; Neuroendocrine Tumors; Paraganglioma; Pathogenicity; Pathway interactions; Patient Care; Patients; Penetrance; Phenotype; Pheochromocytoma; Positioning Attribute; Predisposition; Prevention; Primary Neoplasm; Prognosis; Regulatory Element; Renal Cell Carcinoma; Respiratory Chain; Risk; Role; Sampling; Secondary to; Stromal Neoplasm; Succinate Dehydrogenase; Succinates; Susceptibility Gene; Syndrome; Testing; Therapeutic Intervention; Translations; Variant; base; biobank; cancer prevention; cancer risk; cancer therapy; case control; causal variant; clinical care; curative treatments; design; disorder risk; early childhood; genetic variant; genome wide association study; genome-wide; high risk; molecular marker; patient subsets; personalized medicine; personalized screening; predictive marker; rare variant; response; risk variant; screening; screening guidelines; targeted sequencing; therapeutic target; trait; tumor; working group

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.

项目摘要 晚期或转移性嗜铬细胞瘤/paraganglioma（PGL/PCC）患者的当前疗法为 没有治愈性，也没有已知的分子或遗传标记来预测原发性或转移的渗透率 疾病。尽管大多数患者患有零星的肿瘤，但多达40％的PGL/PCC有遗传原因， 鉴定出至少12个不同的敏感性基因。琥珀酸脱氢酶亚基（SDH）基因 形成线粒体呼吸链的复合物II 富马酸。任何SDHX基因中的种系致病变异都会增加发展遗传性的风险 PGL/PCC综合征。该综合征由多灶性主要PGL/PCC的肾细胞的发展定义 癌和胃肠道肿瘤。 SDHX致病载体中该疾病的渗透率 种系变体每个基因各不相同。此外，没有用于原发性肿瘤发展的预测标记 或转移性疾病。理解基因型和表型之间的差距使临床 筛查和监视的建议很困难，并在现场创造了未满足的需求。目标 该建议是确定开发PGL/PCC的遗传风险环境，以更好地了解 癌症并确定与SDHX相关的PGL/PCC的遗传修饰符直接转换为临床护理 用于预测癌症风险和预后以及鉴定预防癌症的治疗靶标 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 已经组装了最大的已知样品集的1740种系DNA，并匹配了患者的临床数据 与零星和SDHX相关的PGL/PCC以及种系SDHX致病变异的患者 没有PGL/PCC。在AIM 1中，我们将确定PGL/PCC的遗传遗传风险基因座，以更好地理解 通过进行病例控制基因组SNP分析，癌症的遗传病因。在AIM 2中，我们将 确定SDHX致病变体载体的遗传遗传风险修饰符，以开发PGL/PCC 在患有和没有疾病的SDHX载体之间进行病例对照研究。 AIM 3专注于稀有变体 在SDH复合物中，可以是SDHB相关PGL/PCC的修饰符。 SDHB运营商处于最高 发生转移性疾病的风险。最后，使用几种包括EQTL分析和调节的方法 元素分析，我们将确定使用体外功能测定法测试的最可能的因果变异。成功的 鉴定偶发或SDHX相关的PGL/PCC的遗传修饰符将直接转换为临床 通过确定具有个性化筛查方法的风险最高的人并确定癌症的目标 预防和治疗干预。