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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：
10599196
负责人：
Lauren Michelle Fishbein
金额：
$ 34.87万
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/10599196
关键词：
Adrenal Glands Age of Onset American Asian 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 Germ-Line Mutation Glioblastoma Goals Hereditary Paraganglioma Hypoxia Image In Vitro Individual Inherited International Laboratories 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 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 biobank cancer prevention cancer risk cancer therapy case control causal variant clinical care curative treatments design disease prognosis 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 understudied cancer 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.

项目总结

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Presentation, Management, and Outcomes of Urinary Bladder Paraganglioma: Results From a Multicenter Study.

膀胱副神经节瘤的表现、治疗和结果：多中心研究的结果。

DOI：
10.1210/clinem/dgac427
发表时间：
2022
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
0
作者：
Yu,Kai;Ebbehøj,AndreasLadefoged;Obeid,Hiba;Vaidya,Anand;Else,Tobias;Wachtel,Heather;Main,AilsaMaria;Søndergaard,Esben;LehmannChristensen,Louise;Juhlin,Christofer;Calissendorff,Jan;Cohen,DebbieL;Bennett,Bonita;Andersen,Marian
通讯作者：
Andersen,Marian

SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas.

DOI：
10.1016/j.celrep.2022.110453
发表时间：
2022-03-01
期刊：
Cell reports
影响因子：
8.8
作者：
Armstrong N;Storey CM;Noll SE;Margulis K;Soe MH;Xu H;Yeh B;Fishbein L;Kebebew E;Howitt BE;Zare RN;Sage J;Annes JP
通讯作者：
Annes JP

Single-nuclei and bulk-tissue gene-expression analysis of pheochromocytoma and paraganglioma links disease subtypes with tumor microenvironment.