Clinical Relevance of Chromosome 5p/9p/20q/8q Germline Alterations in Glioma

胶质瘤中染色体 5p/9p/20q/8q 种系改变的临床相关性

基本信息

批准号：
8729255
负责人：
Panagiotis Z. Anastasiadis
金额：
$ 36.98万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729255
关键词：
19q 20q 20q13 8q24 9p21 Accounting Adult Glioma Age Anaplastic astrocytoma Applications Grants Astrocytoma CDKN2A gene California Cancer Family Chromosomes Chromosomes, Human, Pair 10 Clinical Collaborations Copy Number Polymorphism Custom Data Development Diagnosis Disease Epidermal Growth Factor Receptor European Family Gender Genetic Genetic Polymorphism Genotype Glioblastoma Glioma Grant Haplotypes Hereditary Melanoma Instruction Learning Malignant neoplasm of brain Mesenchymal Modeling Molecular Morbidity - disease rate Morphology Mutation Outcome PTEN gene Pathologic Patients Penetrance Predisposition Prevalence Prevention Relative Risks Reporting Risk Sampling San Francisco Signs and Symptoms Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Subgroup Syndrome The Cancer Genome Atlas Universities Validation base case control chromosome 7 gain clinically relevant cohort design genetic analysis genome wide association study mRNA Expression mortality next generation sequencing novel oligodendroglioma prospective relating to nervous system research study t(1 19)(q23 p13)tumor

项目摘要

The development of glioblastoma (GBM) has been hypothesized to be associated with relatively common germline alterations with limited penetrance. Recently, two genome-wide association studies (GWAS) using various single nucleotide polymorphism (SNP) array platforms have been performed in gliomas. Collaborating with the group at the University of California at San Francisco (UCSF) we recently reported that SNPs mapping near CDKN2A/B/ARF (9p21) and RTEL1 (20q13) are associated with the development of high grade astrocytomas. In a separate study of patients with gliomas, MD Anderson and European groups observed these associations as well as associations near TERT (5p15) and CCDC26/MLZE (8q24). A re-analysis of UCSF/Mayo data suggests that the RTEL1 (20q13), TERT (5p15) and CCDC26/MLZE (8q24) associations are largely restricted to patients with GBM, anaplastic astrocytoma and with oligodendroglioma, respectively - suggesting that different germline polymorphisms are associated with the development of different glioma subtypes. In this grant application we propose to further validate the germline alteration(s) within and/or near to the CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions that are associated with the development of glioma, to correlate alteration status with somatic genetic and expression alterations, with pathologic variables and with clinical parameters. Our Specific Aims are: Aim 1: Perform detailed germline genetic analysis of the associated CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) regions using three cohorts of prospectively glioma cases and controls to estimate the prevalence and relative risk of known polymorphisms and new alterations. Aim 2: Evaluate the clinical, histopathologic, and molecular pathologic relevance of the germline CDKN2A/B (9p21), TERT (5p15), RTEL1 (20q13) and CCDC26/MLZE (8q24) alterations. This application is designed to validate the alterations in each of the four regions associated with glioma development. Importantly, It will evaluate the clinical, pathologic and molecular pathologic relevance of these alterations.

假设胶质母细胞瘤（GBM）的发展与相对常见渗透率有限的种系改变。最近，使用了两项全基因组关联研究（GWAS）各种单核苷酸多态性（SNP）阵列平台已在神经胶质瘤中进行。与加利福尼亚大学旧金山大学（UCSF）的小组合作，我们最近报告在CDKN2A/B/ARF（9P21）和RTEL1（20Q13）附近的SNP映射与开发有关高级星形胶质细胞瘤。在对神经胶质瘤患者的另一项研究中，MD Anderson和欧洲小组观察到这些关联以及TERT（5p15）和CCDC26/MLZE（8Q24）附近的关联。 UCSF/Mayo数据的重新分析表明RTEL1（20Q13），TERT（5P15）和CCDC26/MLZE （8Q24）关联在很大程度上限于GBM患者，偏长胶质细胞瘤以及与少突齿瘤分别 - 表明不同的种系多态性与不同神经胶质瘤亚型的发展。在此赠款申请中，我们建议进一步验证内部和/或附近的种系改变CDKN2A/B（9p21），TERT（5P15），RTEL1（20Q13）和与神经胶质瘤发展相关的CCDC26/MLZE（8Q24）区域，以相关的改变具有躯体遗传和表达改变的状态，病理变量和临床参数。我们的具体目的是：目标1：对相关的详细种系遗传分析 CDKN2A/B（9P21），TERT（5P15），RTEL1（20Q13）和CCDC26/MLZE（8Q24）区域使用三个同类前瞻性神经胶质瘤病例和对照，以估计已知的患病率和相对风险多态性和新改变。目标2：评估临床，组织病理学和分子病理学种系CDKN2A/B（9P21），TERT（5P15），RTEL1（20Q13）和CCDC26/MLZE的相关性（8Q24）改变。该应用程序旨在验证与神经胶质瘤发育。重要的是，它将评估临床，病理和分子病理相关性这些改变。