Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit street, Boston, MA, USA.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Acta Neuropathol Commun. 2018 Oct 17;6(1):106. doi: 10.1186/s40478-018-0613-2.
TERT promoter (TERTp) mutations are found in the majority of World Health Organization (WHO) grade IV adult IDH wild-type glioblastoma (IDH-wt GBM). Here, we characterized the subset of IDH-wt GBMs that do not have TERTp mutations. In a cohort of 121 adult grade IV gliomas, we identified 109 IDH-wt GBMs, after excluding 11 IDH-mutant cases and one H3F3A -mutant case. Within the IDH-wt cases, 16 cases (14.7%) were TERTp wild-type (TERTp-wt). None of the 16 had BRAF V600E or H3F3A G34 hotspot mutations. When compared to TERTp mutants, patients with TERTp-wt GBMs, were significantly younger at first diagnosis (53.2 years vs. 60.7 years, p = 0.0096), and were more frequently found to have cerebellar location (p = 0.0027). Notably, 9 of 16 (56%) of TERTp-wt GBMs contained a PIK3CA or PIK3R1 mutation, while only 16/93 (17%) of TERTp-mutant GBMs harbored these alterations (p = 0.0018). As expected, 8/16 (50%) of TERTp-wt GBMs harbored mutations in the BAF complex gene family (ATRX, SMARCA4, SMARCB1, and ARID1A), compared with only 8/93 (9%) of TERTp-mutant GBMs (p = 0.0003). Mutations in BAF complex and PI3K pathway genes co-occurred more frequently in TERTp-wt GBMs (p = 0.0002), an association that has been observed in other cancers, suggesting a functional interaction indicative of a distinct pathway of gliomagenesis. Overall, our finding highlights heterogeneity within WHO-defined IDH wild-type GBMs and enrichment of the TERTp-wt subset for BAF/PI3K-altered tumors, potentially comprising a distinct clinical subtype of gliomas.
TERT 启动子 (TERTp) 突变存在于大多数世界卫生组织 (WHO) 四级成人 IDH 野生型胶质母细胞瘤 (IDH-wt GBM) 中。在这里，我们对没有 TERTp 突变的 IDH-wt GBM 亚组进行了特征描述。在 121 例成人四级胶质瘤队列中，我们排除了 11 例 IDH 突变病例和 1 例 H3F3A 突变病例后，确定了 109 例 IDH-wt GBM。在 IDH-wt 病例中，16 例 (14.7%) 为 TERTp 野生型 (TERTp-wt)。这 16 例均无 BRAF V600E 或 H3F3A G34 热点突变。与 TERTp 突变体相比，TERTp-wt GBM 患者的首次诊断年龄明显较小 (53.2 岁 vs. 60.7 岁，p=0.0096)，且更常位于小脑位置 (p=0.0027)。值得注意的是，16 例 TERTp-wt GBM 中有 9 例 (56%) 含有 PIK3CA 或 PIK3R1 突变，而 93 例 TERTp 突变型 GBM 中只有 16 例 (17%) 存在这些改变 (p=0.0018)。正如预期的那样，16 例 TERTp-wt GBM 中有 8 例 (50%) 存在 BAF 复合物基因家族 (ATRX、SMARCA4、SMARCB1 和 ARID1A) 突变，而 93 例 TERTp 突变型 GBM 中只有 8 例 (9%) 存在这些改变 (p=0.0003)。BAF 复合物和 PI3K 通路基因的突变在 TERTp-wt GBM 中更常同时发生 (p=0.0002)，这种关联在其他癌症中也观察到过，表明存在功能相互作用，提示胶质母细胞瘤发生的一种独特途径。总的来说，我们的研究结果强调了在 WHO 定义的 IDH 野生型 GBM 中存在异质性，以及 TERTp-wt 亚组富含 BAF/PI3K 改变的肿瘤，这可能构成了胶质瘤的一个独特临床亚型。
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