Abstract

Background

Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype.

Methods

A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10⁻⁸.

Results

Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10⁻¹⁰). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10⁻⁸). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10⁻⁹). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10⁻¹⁰).

Conclusions

Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

中文翻译：

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按分子亚型划分的成人弥漫性胶质瘤 GWAS 鉴定了 D2HGDH 和 FAM20C 的变异体。

 抽象的

 背景

二十五个种系变异与成人弥漫性神经胶质瘤相关，其中一些变异已被证明与神经胶质瘤的特定亚型相关。我们假设，如果按分子亚型进行全基因组关联研究（GWAS），则可以鉴定出其他种系变异。

 方法

发现集中总共使用了 1320 个神经胶质瘤病例和 1889 个对照，验证集中使用了 799 个神经胶质瘤病例和 808 个对照。根据异柠檬酸脱氢酶 ( IDH ) 突变、端粒酶逆转录酶 ( TERT ) 启动子突变和 1p/19q 共缺失的组合，将神经胶质瘤病例分为分子亚型。将逻辑回归应用于发现集和验证集，以测试变体与每个亚型的关联。随后使用 5 × 10 ^-8的全基因组P值阈值进行荟萃分析。

 结果

2 号染色体上的 D-2-羟基戊二酸脱氢酶 ( D2HGDH ) 内或附近的 9 个变异在IDH突变神经胶质瘤中具有全基因组显着性（最显着的是 rs5839764，meta P = 2.82 × 10 ^-10 ）。通过 1p/19q 共缺失状态进一步分层， D2HGDH的一种变异在IDH突变的非共缺失神经胶质瘤中具有全基因组显着性（rs1106639，meta P = 4.96 × 10 ^-8 ）。通过TERT突变进一步分层，7 号染色体上FAM20C （序列相似性为 20 的家族，成员 C）附近的一个变异在具有IDH突变、 TERT突变和 1p/19q 联缺失的神经胶质瘤中具有全基因组显着性（rs111976262，meta P = 9.56） × 10 ^-9 )。在IDH野生型胶质瘤中，20 号染色体上靠近端粒延伸解旋酶 1 ( RTEL1 ) 调节因子的GMEB2内或附近的 36 个变异在全基因组范围内具有显着性（最显着的是 rs4809313，meta P = 2.60 × 10 ^-10 ）。

 结论

按分子亚型进行 GWAS 发现了 2 个新区域和RTEL1附近的一个候选独立区域，这些区域与特定的神经胶质瘤分子亚型相关。