High frequency of H3K27M immunopositivity in adult thalamic glioblastoma

Abstract

Adult thalamic glioblastomas (GBM) are uncommon tumors with limited available molecular data. One of the reported molecular alterations in these tumors is the H3K27M mutation. It has been documented that H3K27M mutation is found in a high proportion of pediatric thalamic gliomas. In this study, we have analyzed the molecular alterations exclusive to adult thalamic GBM. This is a 6 years retrospective study of adult thalamic GBM patients who underwent surgical decompression of the tumor. Clinical data were obtained from the case records. Immunohistochemistry (IHC) was performed on the tumors using antibodies directed against the gene products of R132H mutant isocitrate dehydrogenase 1 (IDH1), alpha‐thalassemia/mental retardation X‐linked (ATRX), p53, H3K27M, H3K27me3, and V600E mutant BRAF. Molecular analyses were carried out to detect other IDH1 and IDH2 mutations, O6‐methylguanine‐DNA‐methyltransferase gene (MGMT) promoter methylation, and epidermal growth factor gene (EGFR) and telomerase reverse transcriptase gene (TERT) promoter mutations. A total of 42 cases of adult thalamic GBM were studied. The mean age of presentation was 42 years with age range of 19–58 years. Male predominance was noted. All the tumors were IDH wild‐type, BRAF (V600E)‐immunonegative and unmethylated for MGMT promoter. H3K27M immunopositivity was noted in 60% of tumors. Of these 33.3% were from older adults above the age of 50 years. Of the H3K27M‐immunopositive cases, ATRX loss of expression was seen in 32%, p53 immunopositivity in 24% and EGFR amplification in 12%. Higher frequency of TERT promoter mutations was noted in H3K27M‐immunonegative cases (58.8%) compared to immunopositive cases (20%). Ours is one of the few studies elucidating the molecular alterations exclusive to adult thalamic GBM. We show a high frequency of H3K27M immunopositivity, suggestive of its mutational status in these tumors, including in older adults.

Maximal surgical resection and adjuvant surgical technique to prolong the survival of adult patients with thalamic glioblastoma

“…Since this study contains only a relatively small number of surgical resection cases, further research with a larger number is needed. The H3K27m mutation is an important prognostic factor for thalamic GBM [42,43], but it has not been included in this study because it has only been tested in a very small number of cases in our institution. More molecular diagnosis should be included in future studies.…”

A tailored next‐generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas

“…Currently, diagnostic neuropathology laboratories test for selected biomarkers individually, including mutations in IDH1/2 , the ATRX chromatin remodeler gene ( ATRX) , the telomerase reverse transcriptase gene ( TERT ), H3 ‐K27M, and the B‐Raf proto‐oncogene, serine/threonine kinase gene ( BRAF ), as well as 1p/19q codeletion. This involves various testing methods, including immunohistochemistry with mutation‐specific antibodies such as those against IDH1 ‐R132H, BRAF ‐V600E, and H3 ‐K27M, 11‐13 conventional Sanger sequencing or pyrosequencing of tumor DNA for detection of mutations, FISH, CGH, chromogenic in situ hybridization (CISH), PCR‐based microsatellite analysis, real‐time comparative quantitative PCR; and multiplex ligation‐dependent probe amplification for detection of 1p/19q codeletion 14‐18 . Immunohistochemical (IHC) assays for IDH1 ‐R132H, BRAF ‐V600E, and H3 ‐K27M are relatively sensitive and specific, but there is a non‐trivial rate of discordance.…”

Expression and Prognostic Value of ARID5A and its Correlation With Tumor-Infiltrating Immune Cells in Glioma

“…Mutations in the P53 gene can lead to uncontrolled cell proliferation, which can lead to cancer ( 32 ). Accumulating evidence indicates that the occurrence and development of glioma are closely related to the expression level of P53 ( 33 , 34 ). The JAK-STAT signaling pathway is one of the classic intracellular signal transduction pathways that regulates cell proliferation, differentiation, and apoptosis and also plays an important role in the tumorigenesis ( 35 , 36 ).…”