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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要目前针对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疗作用，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症的外显率尽管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，已鉴定出至少 12 个不同的易感基因琥珀酸脱氢酶亚基 (SDH) 基因。形成线粒体呼吸链的复合体 II，并参与克雷布循环转化琥珀酸任何 SDHx 基因的种系致病性变异都会增加患遗传性疾病的风险。 PGL/PCC 综合征该综合征的定义是多灶性原发性 PGL/PCC、肾细胞的发展。 SDHx 致病菌携带者的癌症和胃肠道间质瘤的外显率。此外，没有原发性肿瘤发展的预测标记。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，并且在该领域造成了未满足的需求。该提案旨在确定开发 PGL/PCC 的遗传风险位点，以更好地了解该疾病的病因学癌症并确定 SDHx 相关 PGL/PCC 的遗传修饰因子，以直接转化为临床护理用于预测癌症风险和预后以及确定癌症预防的治疗靶点利用国际美国-澳大利亚-亚洲肾上腺联盟 (A5) 联盟，我们组装了已知最大的 1740 个种系 DNA 样本集，并匹配了患者的临床数据散发性和 SDHx 相关 PGL/PCC 以及具有种系 SDHx 致病性变异的患者在目标 1 中，我们将确定 PGL/PCC 的遗传风险位点，以更好地了解 PGL/PCC。在目标 2 中，我们将通过进行病例对照全基因组 SNP 分析来了解癌症的遗传病因。确定 SDHx 致病性变异携带者的遗传性遗传风险修饰因子以开发 PGL/PCC 在患有和未患有疾病的 SDHx 携带者之间进行病例对照研究，目标 3 重点关注罕见变异。在 SDH 复合体中，它可能是 SDHB 相关 PGL/PCC 载体的修饰符。最后，使用包括 eQTL 分析和监管在内的多种方法。元素分析，我们将确定最有可能的因果变异，以通过体外功能分析进行成功测试。散发性或 SDHx 相关 PGL/PCC 遗传修饰的鉴定将直接转化为临床通过个性化筛查方法确定风险最高的人群并确定癌症目标来提供护理预防和治疗干预。