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

胶质母细胞瘤(GBM)的发展被认为与相对常见的 生殖系的改变与有限的外显。最近，两项全基因组关联研究(GWAS)使用 各种单核苷酸多态(SNP)阵列平台已经在胶质瘤中进行了研究。 与加州大学旧金山分校(UCSF)的该小组合作，我们最近报道 CDKN2A/B/ARF(9p21)和RTEL1(20q13)附近的SNPs与遗传相关 高级别星形细胞瘤。在另一项针对胶质瘤患者的单独研究中，MD Anderson和European 研究小组观察到了这些关联以及TERT(5p15)和CCDC26/MLZE(8q24)附近的关联。 对加州大学旧金山分校/梅奥大学数据的重新分析表明，RTEL1(20q13)、TERT(5p15)和CCDC26/MLZE (8q24)相关性主要限于GBM、间变性星形细胞瘤和 分别为少突胶质细胞瘤--表明不同的生殖系多态与 不同胶质瘤亚型的发生。在这项拨款申请中，我们建议进一步验证 CDKN2A/B(9p21)、TERT(5p15)、RTEL1(20q13)和/或附近的生殖系改变(S) 与胶质瘤发生发展相关的CCDC26/MLZE(8q24)区域与相关改变 与体细胞遗传和表达改变、病理变量和临床相关的状况 参数。我们的具体目标是：目标1：对相关基因进行详细的种系遗传分析 CDKN2A/B(9p21)、TERT(5p15)、RTEL1(20q13)和CCDC26/MLZE(8q24)区域 前瞻性脑胶质瘤病例和对照估计已知的患病率和相对风险 多态和新的变化。目的2：评价该病的临床、组织病理学和分子病理学。 CDKN2A/B(9p21)、TERT(5p15)、RTEL1(20q13)与CCDC26/MLZE(8q24)的相关性 改装。此应用程序旨在验证与关联的四个区域中的每个区域中的更改 神经胶质瘤的发展。重要的是，它将评估临床、病理和分子病理学的相关性。 这些变化。

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.