A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas

作者：Venneti Sriram^*; Santi Mariarita; Felicella Michelle Madden; Yarilin Dmitry; Phillips Joanna J; Sullivan Lisa M; Martinez Daniel; Perry Arie; Lewis Peter W; Thompson Craig B; Judkins Alexander R

来源：Acta Neuropathologica, 2014, 128(5): 743-753.

DOI：10.1007/s00401-014-1338-3

• Pediatric glioblastoma
• H3F3A mutation
• K27M mutation
• H3K27me3
• Diagnostic biomarker
• Prognosis
• Methylation
• Epigenetics

Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that similar to 30 % of pediatric GBM and similar to 80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM.

• 出版日期2014-11