Urbschat Steffi, Sippl Christoph, Engelhardt Jana, Kammers Kai, Oertel Joachim, Ketter Ralf
Department of Neurosurgery, Saarland University, 66421 Homburg/Saar, Germany.
Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Mol Cytogenet. 2017 May 4;10:16. doi: 10.1186/s13039-017-0317-5. eCollection 2017.
To assess the influence of molecular markers with potential prognostic value to groups of patients with newly diagnosed glioblastoma patients were examined: group A with 36 patients (surgical resection plus standard combined chemoradiotherapy) and group B with 36 patients (surgical resection, standard combined chemoradiotherapy plus carmustine wafer implantation). Our aim was to determine chromosomal alterations, methylation status of MGMT, p15, and p16 (CDKN2A) in order to analyse the influence on patient survival time as well as radio- and chemotherapy responses. Promoter hypermethylation of MGMT, p16, and p15 genes were determined by MS-PCR. Comparative genomic hybridisation (CGH) analyses were performed with isolated, labelled DNA of each tumor to detect genetic alterations.
Age of onset of the disease showed a significant effect on overall survival (OS) ( < 0.0001). Additional treatment with carmustine wafer (group B) compared to the control group (group A) did not result in improved OS ( = 0.562). Patients with a methylated MGMT promotor showed a significant longer OS compared to those patients with unmethylated MGMT promotor ( = 0.041). Subgroup analyses revealed that patients with methylated p15 showed a significant shorter OS when administered to group B rather than in group A ( = 0.0332). In patients additionally treated with carmustine wafer an amplification of 4q12 showed a significant impact on a reduced OS ( = 0.00835). In group B, a loss of 13q was significantly associated with a longer OS ( = 0.0364). If a loss of chromosome 10 occurred, patients in group B showed a significantly longer OS ( = 0.0123).
A clinical benefit for the widespread use of additional carmustine wafer implantation could not be found. However, carmustine wafer implantation shows a significantly improved overall survival if parts of chromosome 10 or chromosome 13 are deleted. In cases of 4q12 amplification and in cases of a methylated p15 promotor, the use of carmustine wafers is especially not recommended. The MGMT promoter methylation is a strong prognostic Biomarker for benefit from temozolomide and BCNU chemotherapy.
为评估具有潜在预后价值的分子标志物对新诊断的胶质母细胞瘤患者群体的影响，对患者进行了检查：A组36例患者（手术切除加标准联合放化疗）和B组36例患者（手术切除、标准联合放化疗加卡莫司汀晶片植入）。我们的目的是确定染色体改变、MGMT、p15和p16（CDKN2A）的甲基化状态，以分析对患者生存时间以及放疗和化疗反应的影响。通过甲基化特异性聚合酶链反应（MS-PCR）测定MGMT、p16和p15基因的启动子高甲基化。使用每个肿瘤分离的标记DNA进行比较基因组杂交（CGH）分析以检测基因改变。
疾病发病年龄对总生存期（OS）有显著影响（<0.0001）。与对照组（A组）相比，卡莫司汀晶片的额外治疗（B组）并未改善总生存期（=0.562）。与MGMT启动子未甲基化的患者相比，MGMT启动子甲基化的患者总生存期显著更长（=0.041）。亚组分析显示，甲基化p15的患者在B组而非A组接受治疗时总生存期显著缩短（=0.0332）。在接受卡莫司汀晶片额外治疗的患者中，4q12扩增对总生存期缩短有显著影响（=0.00835）。在B组中，13q缺失与总生存期延长显著相关（=0.0364）。如果发生10号染色体缺失，B组患者的总生存期显著更长（=0.0123）。
未发现广泛使用额外的卡莫司汀晶片植入有临床益处。然而，如果10号染色体或13号染色体部分缺失，卡莫司汀晶片植入显示总生存期显著改善。在4q12扩增的情况下以及在p15启动子甲基化的情况下，尤其不建议使用卡莫司汀晶片。MGMT启动子甲基化是从替莫唑胺和卡氮芥化疗中获益的强有力的预后生物标志物。
