Glioblastoma multiforme (GBM) is the most aggressive and prevalent form of brain cancer, with an expected survival of 12–15 months following diagnosis. GBM affects the glial cells of the central nervous system, which impairs regular brain function including memory, hearing, and vision. GBM has virtually no long-term survival even with treatment, requiring novel strategies to understand disease progression. Here, we identified a somatic mutation in OR2T7, a G-protein-coupled receptor (GPCR), that correlates with reduced progression-free survival for glioblastoma (log rank p-value = 0.05), suggesting a possible role in tumor progression. The mutation, D125V, occurred in 10% of 396 glioblastoma samples in The Cancer Genome Atlas, but not in any of the 2504 DNA sequences in the 1000 Genomes Project, suggesting that the mutation may have a deleterious functional effect. In addition, transcriptome analysis showed that the p38α mitogen-activated protein kinase (MAPK), c-Fos, c-Jun, and JunB proto-oncogenes, and putative tumor suppressors RhoB and caspase-14 were underexpressed in glioblastoma samples with the D125V mutation (false discovery rate < 0.05). Molecular modeling and molecular dynamics simulations have provided preliminary structural insight and indicate a dynamic helical movement network that is influenced by the membrane-embedded, cytofacial-facing residue 125, demonstrating a possible obstruction of G-protein binding on the cytofacial exposed region. We show that the mutation impacts the “open” GPCR conformation, potentially affecting G_α-subunit binding and associated downstream activity. Overall, our findings suggest that the Val125 mutation in OR2T7 could affect glioblastoma progression by downregulating GPCR-p38 MAPK tumor-suppression pathways and impacting the biophysical characteristics of the structure that facilitates G_α-subunit binding. This study provides the theoretical basis for further experimental investigation required to confirm that the D125V mutation in OR2T7 is not a passenger mutation. With validation, the aforementioned mutation could represent an important prognostic marker and a potential therapeutic target for glioblastoma.

多形性胶质母细胞瘤 (GBM) 是最具侵袭性和最常见的脑癌形式，诊断后预计生存期为 12-15 个月。GBM 会影响中枢神经系统的神经胶质细胞，从而损害包括记忆、听力和视力在内的正常大脑功能。即使经过治疗，GBM 也几乎无法长期存活，因此需要新的策略来了解疾病进展。在这里，我们发现了 OR2T7（一种 G 蛋白偶联受体 (GPCR)）中的体细胞突变，该突变与胶质母细胞瘤无进展生存期缩短相关（对数秩 p 值 = 0.05），表明其可能在肿瘤进展中发挥作用。D125V 突变出现在癌症基因组图谱中 396 个胶质母细胞瘤样本中的 10% 中，但在 1000 个基因组计划中的 2504 个 DNA 序列中没有出现，这表明该突变可能具有有害的功能影响。此外，转录组分析表明，D125V 的胶质母细胞瘤样本中 p38 α 丝裂原激活蛋白激酶 (MAPK)、c-Fos、c-Jun 和 JunB 原癌基因以及推定的肿瘤抑制因子 RhoB 和 caspase-14 表达不足突变（错误发现率 < 0.05）。分子建模和分子动力学模拟提供了初步的结构见解，并表明动态螺旋运动网络受到膜嵌入、面向细胞面的残基 125 的影响，表明细胞面暴露区域上的 G 蛋白结合可能受到阻碍。我们发现该突变影响“开放”GPCR 构象，可能影响 G _α亚基结合和相关下游活性。总体而言，我们的研究结果表明，OR2T7 中的 Val125 突变可能通过下调 GPCR-p38 MAPK 肿瘤抑制途径并影响促进 G α 亚基结合的结构的生物物理特征来影响胶质母细胞瘤_进展。该研究为进一步的实验研究提供了理论基础，以确认OR2T7中的D125V突变不是过客突变。经过验证，上述突变可能代表胶质母细胞瘤的重要预后标志物和潜在治疗靶点。