Xiu Joanne, Piccioni David, Juarez Tiffany, Pingle Sandeep C, Hu Jethro, Rudnick Jeremy, Fink Karen, Spetzler David B, Maney Todd, Ghazalpour Anatole, Bender Ryan, Gatalica Zoran, Reddy Sandeep, Sanai Nader, Idbaih Ahmed, Glantz Michael, Kesari Santosh
Caris Life Sciences, Phoenix, AZ, USA.
Neuro-Oncology Program, Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
Oncotarget. 2016 Apr 19;7(16):21556-69. doi: 10.18632/oncotarget.7722.
Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.
胶质母细胞瘤（GBM）是最具侵袭性且最常见的胶质瘤形式，预后极差，治疗选择有限。我们分析了1035例GBM肿瘤中提示对治疗有反应的临床相关分子异常。我们的分析显示，在48个检测基因中有39个发生了突变。免疫组化显示，19%的肿瘤中存在程序性死亡受体配体1（PD-L1）表达，46%的肿瘤中存在程序性死亡受体1（PD-1）表达。43%的肿瘤出现O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）甲基化，19%的肿瘤出现表皮生长因子受体III型变异体（EGFRvIII），2%的肿瘤出现1号染色体短臂1区和19号染色体长臂1区共缺失（1p19q）。TP53突变与并发突变相关，而异柠檬酸脱氢酶1（IDH1）突变与MGMT甲基化和TP53突变相关，且与EGFRvIII突变相互排斥。与世界卫生组织（WHO）III级星形细胞瘤相比，GBM中可见不同的生物标志物谱，提示生物学特性不同，治疗方法可能也不同。对17例异时性配对肿瘤的分析显示，生物标志物频繁变化，包括MGMT甲基化和EGFR异常，这表明需要重新活检以进行肿瘤分析，从而指导后续治疗。在按年龄定义的GBM亚组中，MGMT甲基化、孕激素受体（PR）和拓扑异构酶1（TOPO1）是显著的预后标志物。本研究是目前关于临床GBM肿瘤规模最大的生物标志物研究，采用了多种技术来检测基因突变、扩增、蛋白表达和启动子甲基化。这些数据将为未来基于个性化生物标志物的临床试验规划提供信息，并基于肿瘤生物标志物确定有效的治疗方法。
