TERT promoter wild-type glioblastomas show distinct clinical features and frequent PI3K pathway mutations

Abstract

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0613-2) contains supplementary material, which is available to authorized users.

TERT promoter mutation associated with multifocal phenotype and poor prognosis in patients with IDH wild-type glioblastoma

“…Recently, Williams et al reported TERT p wild-type GBMs showed frequent PI3K pathway and BAF complex gene family ( ATRX , SMARCA4 , SMARCB1 , and ARID1A ) mutations. 38 Our data also suggest that TERT p wild-type GBMs are genetically distinct from TERT p-mutant GBMs.…”

Revisiting Telomere Shortening in Cancer

“…In accordance with this observation, TERT promoter mutations are mutually exclusive with the mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX), death domain associated protein (DAXX) or switch/sucrose non-fermentable (SWI/SNF) related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 1 (SMARCA1), which are chromatin remodeling proteins associated with ALT pathway activation [49,50,51,52]. In addition, ARID1A and PIK3CA mutations also tend to be mutually exclusive with TERT promoter mutations in ovarian clear cell carcinoma or glioma [53,54]. These proteins regulate telomerase activity epigenetically or post-translationally.…”

The Solo Play of TERT Promoter Mutations

“…Consistent with this view, Phosphatidyl Inositol Kinase 3 (PIK3) CA and PIK3 Receptor 1 (PIK3R1) mutations are recorded in 50% of GBM with wt TERTp and tend to be mutually exclusive with TERTp mutations in ovarian clear cell carcinoma [79,86,132]. The PIK3CA/Akt signaling pathway is involved in cellular self-renewal in embryonic stem cells and cancer stem cells [135], as well as in TERT Ser227 and Ser824 phosphorylation, subsequent nuclear translocation, and cellular transformation [25][26][27][28].…”

“…APOBEC3 mutations are highly prevalent in ovarian and HPV-associated cervical and oral SCC [125][126][127], as well as in HCC and in cirrhotic lesions [121,134]. A role for APOBEC and aging-associated de-aminations is consistent with potentially increased accessibility of the −124 position to DNA binding proteins and with the association of TERTp mutations with older age at diagnosis in GBM, melanoma, and PTC [52,57,60,63,64,77,79,80,82,86,88,98,[100][101][102]. These observations therefore raise the possibility that UV-driven lesions account for TERTp mutations in skin cancers, while APOBEC and age-driven de-aminations account for the −124 C>T mutation in other cancers.…”

“…TERTp mutations have been recorded in a wide range of solid cancers. They are present in primary gliomas and glioblastoma multiforme (GBM), oligodendrogliomas and astrocytomas [10,40,[52][53][54]57,58,60,64,65,[77][78][79][80][81][82][83][84][85][86], melanomas, cutaneous basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [49][50][51][52]55,[87][88][89][90][91], myxoid liposarcomas [77], urothelial bladder carcinoma [50,57,78,[92][93][94], hepatocellular carcinoma (HCC) [50,57,62,[95][96][97], and thyroid cancers [98][99][100][101][102]…”