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

胶质母细胞瘤（GBM）的发展被假设与相对常见的 生殖系改变，具有有限的遗传变异。最近，两项全基因组关联研究（GWAS）使用 已经在神经胶质瘤中进行了各种单核苷酸多态性（SNP）阵列平台。 最近，我们与加州大学弗朗西斯科分校（UCSF）的研究小组合作， CDKN 2A/B/ARF（9 p21）和RTEL 1（20 q13）附近的SNPs与 高级别星形细胞瘤在另一项神经胶质瘤患者的研究中，MD安德森和欧洲神经胶质瘤研究人员发现， 研究组观察到这些关联以及在TERT（5 p15）和CCDC 26/MLZE（8 q24）附近的关联。 对UCSF/马约数据的重新分析表明，RTEL 1（20 q13）、TERT（5 p15）和CCDC 26/MLZE （8 q24）关联主要限于GBM、间变性星形细胞瘤和 少突胶质细胞瘤-这表明不同的生殖系多态性与少突胶质细胞瘤相关。 不同胶质瘤亚型的发展。在这项拨款申请中，我们建议进一步验证 CDKN 2 A/B（9p21）、TERT（5p15）、RTEL 1（20 q13）和 CCDC 26/MLZE（8 q24）区域与胶质瘤的发展相关，以关联改变 体细胞遗传和表达改变的状态，病理变量和临床 参数我们的具体目标是：目标1：进行详细的生殖系遗传分析的相关 CDKN 2 A/B（9 p21）、TERT（5 p15）、RTEL 1（20 q13）和CCDC 26/MLZE（8 q24）区域，使用三个队列， 前瞻性胶质瘤病例和对照，以估计已知的 多态性和新的改变。目的2：评估临床、组织病理学和分子病理学 生殖系CDKN 2 A/B（9 p21）、TERT（5 p15）、RTEL 1（20 q13）和CCDC 26/MLZE（8 q24）的相关性 改变。此应用程序旨在验证与以下各项相关的四个区域中的每一个中的改变： 神经胶质瘤发展重要的是，它将评估临床，病理和分子病理学相关性 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.