Sharp Amanda K, Newman David, Libonate Gianna, Borns-Stern Mary, Bevan David R, Brown Anne M, Anandakrishnan Ramu
Interdisciplinary Program of Genetics, Bioinformatics, and Computational Biology (GBCB), Virginia Tech, Blacksburg, Virginia.
Biomedical Sciences, Edward Via College of Osteopathic Medicine (VCOM), Blacksburg, Virginia.
Biophys J. 2022 Oct 4;121(19):3706-3718. doi: 10.1016/j.bpj.2022.05.009. Epub 2022 May 10.
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-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-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，诊断后预期生存期为12至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脑功能。即使经过治疗，GBM实际上也没有长期生存率，需要新的策略来了解疾病进展。在此，我们在一种G蛋白偶联受体（GPCR）OR2T7中鉴定出一种体细胞突变，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），提示其在肿瘤进展中可能发挥作用。该突变D125V出现在癌症基因组图谱中396个胶质母细胞瘤样本的10%中，但在千人基因组计划的2504个DNA序列中均未出现，这表明该突变可能具有有害的功能效应。此外，转录组分析显示，在具有D125V突变的胶质母细胞瘤样本中，p38α丝裂原活化蛋白激酶（MAPK）、c-Fos、c-Jun和JunB原癌基因以及假定的肿瘤抑制因子RhoB和半胱天冬酶-14表达下调（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，并表明存在一个动态螺旋运动网络，该网络受膜嵌入的、面向细胞质的第125位残基影响，这表明在细胞质暴露区域可能存在G蛋白结合障碍。我们表明该突变影响“开放”的GPCR构象，可能影响G亚基结合及相关的下游活性。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亚基结合的结构的生物物理特性来影响胶质母细胞瘤的进展。本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突变不是一个过客突变。经过验证，上述突变可能代表胶质母细胞瘤的一个重要预后标志物和潜在治疗靶点。
