进展性/高级别脑膜瘤中的肿瘤内异质性和启动子突变
Intratumoral heterogeneity and promoter mutations in progressive/higher-grade meningiomas.
作者信息
Juratli Tareq A, Thiede Christian, Koerner Mara V A, Tummala Shilpa S, Daubner Dirk, Shankar Ganesh M, Williams Erik A, Martinez-Lage Maria, Soucek Silke, Robel Katja, Penson Tristan, Krause Mechthild, Appold Steffen, Meinhardt Matthias, Pinzer Thomas, Miller Julie J, Krex Dietmar, Ely Heather A, Silverman Ian M, Christiansen Jason, Schackert Gabriele, Wakimoto Hiroaki, Kirsch Matthias, Brastianos Priscilla K, Cahill Daniel P
机构信息
Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
Department of Neurosurgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
出版信息
Oncotarget. 2017 Nov 24;8(65):109228-109237. doi: 10.18632/oncotarget.22650. eCollection 2017 Dec 12.
BACKGROUND
Recent studies have reported mutations in the telomerase reverse transcriptase promoter (p) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene alterations in a cohort of patients with progressive/higher-grade meningiomas.
METHODS
We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients. On initial diagnoses, the meningiomas spanned all WHO grades (3 grade I, 13 grade II and 10 grade III). The tumor samples were screened for p and mutations, and rearrangements. Additionally, p was sequenced in a separate cohort of 19 patients with radiation-associated meningiomas. We examined the impact of mutational status on patients' progression and overall survival.
RESULTS
Somatic p mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in p mutation status was noted. In 4 patients, p mutations were detected in recurrent specimens but not in the available specimens of the first surgery. Additionally, a gene fusion () was found in one sample. In contrary, none of the investigated samples harbored an or mutation. In the cohort of radiation-induced meningiomas, p mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of p mutations had a substantially shorter OS than their p wild-type counterparts (2.7 years, 95% CI 0.9 - 4.5 years versus 10.8 years, 95% CI 7.8 -12.8 years, p=0.003).
CONCLUSIONS
In progressive/higher-grade meningiomas,p mutations are associated with poor survival, supporting a model in which selection of this alteration is a harbinger of aggressive tumor development. In addition, we observe spatial intratumoral heterogeneity of p mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of p mutations may define patients with more aggressive meningiomas. Stratification for alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.
背景
近期研究报道了脑膜瘤中端粒酶逆转录酶启动子（p）的突变。我们试图确定一组进展性/高级别脑膜瘤患者端粒基因改变的频率、克隆性及临床意义。
方法
我们对26例世界卫生组织（WHO）III级脑膜瘤患者的64个时间和区域不同的标本进行了特征分析。初次诊断时，脑膜瘤涵盖了所有WHO级别（3例I级、13例II级和10例III级）。对肿瘤样本进行p和突变筛查以及重排检测。此外，在另一组19例放射性脑膜瘤患者中对p进行测序。我们研究了突变状态对患者进展和总生存的影响。
结果
在6例患者（6/26 = 23%）中检测到体细胞p突变。注意到p突变状态存在区域内肿瘤异质性。在4例患者中，复发病例标本中检测到p突变，但首次手术的可用标本中未检测到。此外，在一个样本中发现了一种基因融合（）。相反，所研究的样本均未携带或突变。在放射性诱导脑膜瘤队列中，2例患者（10.5%）检测到p突变。重要的是，我们发现出现p突变的患者总生存期明显短于p野生型患者（2.7年，95%可信区间0.9 - 4.5年对10.8年，95%可信区间7.8 - 12.8年，p = 0.003）。
结论
在进展性/高级别脑膜瘤中，p突变与生存不良相关，支持这样一种模型，即这种改变的选择是侵袭性肿瘤发展的先兆。此外，我们观察到p突变状态的空间肿瘤内异质性，与肿瘤发生过程中这种晚期出现的模型一致。因此，p突变的早期检测可能有助于确定侵袭性更强的脑膜瘤患者。在未来进展性/高级别脑膜瘤的临床试验中应采用针对改变的分层。
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