The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, 27710, NC, USA.
Department of Pathology, Duke University Medical Center, Durham, 27710, NC, USA.
Nat Commun. 2018 May 25;9(1):2087. doi: 10.1038/s41467-018-04448-6.
The majority of glioblastomas can be classified into molecular subgroups based on mutations in the TERT promoter (TERTp) and isocitrate dehydrogenase 1 or 2 (IDH). These molecular subgroups utilize distinct genetic mechanisms of telomere maintenance, either TERTp mutation leading to telomerase activation or ATRX-mutation leading to an alternative lengthening of telomeres phenotype (ALT). However, about 20% of glioblastomas lack alterations in TERTp and IDH. These tumors, designated TERTp-IDH glioblastomas, do not have well-established genetic biomarkers or defined mechanisms of telomere maintenance. Here we report the genetic landscape of TERTp-IDH glioblastoma and identify SMARCAL1 inactivating mutations as a novel genetic mechanism of ALT. Furthermore, we identify a novel mechanism of telomerase activation in glioblastomas that occurs via chromosomal rearrangements upstream of TERT. Collectively, our findings define novel molecular subgroups of glioblastoma, including a telomerase-positive subgroup driven by TERT-structural rearrangements (IDH-TERT), and an ALT-positive subgroup (IDH-ALT) with mutations in ATRX or SMARCAL1.
大多数胶质母细胞瘤可以根据 TERT 启动子 (TERTp) 和异柠檬酸脱氢酶 1 或 2 (IDH) 的突变分为分子亚群。这些分子亚群利用不同的端粒维持遗传机制，要么是 TERTp 突变导致端粒酶激活，要么是 ATRX 突变导致端粒延长的替代表型 (ALT)。然而，约 20%的胶质母细胞瘤缺乏 TERTp 和 IDH 的改变。这些肿瘤被指定为 TERTp-IDH 胶质母细胞瘤，它们没有明确的遗传生物标志物或端粒维持的定义机制。在这里，我们报告了 TERTp-IDH 胶质母细胞瘤的遗传景观，并确定了 SMARCAL1 失活突变是 ALT 的一种新的遗传机制。此外，我们还发现了一种新的端粒酶激活机制，它发生在 TERT 上游的染色体重排中。总的来说，我们的研究结果定义了胶质母细胞瘤的新分子亚群，包括由 TERT 结构重排驱动的端粒酶阳性亚群 (IDH-TERT) 和具有 ATRX 或 SMARCAL1 突变的 ALT 阳性亚群 (IDH-ALT)。
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