Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas

被引：116

作者：

Bechet, Denise ^{[1
,2
]}

Gielen, Gerrit G. H. ^{[3
]}

Korshunov, Andrey ^{[4
]}

Pfister, Stefan M. ^{[5
]}

Rousso, Caterina ^{[6
]}

Faury, Damien ^{[6
]}

Fiset, Pierre-Olivier ^{[7
]}

Benlimane, Naciba

Lewis, Peter W. ^{[8
]}

Lu, Chao ^{[9
]}

Allis, C. David ^{[9
]}

Kieran, Mark W. ^{[10
]}

Ligon, Keith L. ^{[11
]}

Pietsch, Torsten ^{[3
]}

Ellezam, Benjamin ^{[12
,13
]}

Albrecht, Steffen ^{[7
,14
]}

Jabado, Nada ^{[1
,2
,6
]}

机构：

[1] McGill Univ, Dept Expt Med, Montreal, PQ H3Z 2Z3, Canada

[2] McGill Univ, Dept Human Genet, Montreal, PQ H3Z 2Z3, Canada

[3] Univ Bonn, Med Ctr, Inst Neuropathol, D-53127 Bonn, Germany

[4] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, Heidelberg, Germany

[5] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[6] McGill Univ, Dept Pediat, Ctr Hlth, Montreal Childrens Hosp, Montreal, PQ H3Z 2Z3, Canada

[7] McGill Univ, Montreal Childrens Hosp, Ctr Hlth, Dept Pathol, Montreal, PQ H3Z 2Z3, Canada

[8] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biomol Chem, Madison, WI USA

[9] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10021 USA

[10] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Hematol Oncol,Dept Pediat Oncol,Boston, Boston, MA 02115 USA

[11] Harvard Univ, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA

[12] Univ Montreal, Dept Pathol, CHU Ste Justine, Montreal, PQ H3C 3J7, Canada

[13] Hop Ste Justine, Montreal, PQ, Canada

[14] Montreal Childrens Hosp, Montreal, PQ H3H 1P3, Canada

来源：

ACTA NEUROPATHOLOGICA | 2014年 / 128卷 / 05期

关键词：

K27M; Histone; 3; variants; IHC; K27; trimethylation; High-grade astrocytomas; INTRINSIC PONTINE GLIOMA; ACTIVATING ACVR1 MUTATIONS; PEDIATRIC GLIOBLASTOMA; DISTINCT SUBGROUPS; SOMATIC MUTATIONS; K27M MUTATION; MEDULLOBLASTOMA; H3F3A; TUMORS; EXPRESSION;

D O I：

10.1007/s00401-014-1337-4

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Studies in pediatric high-grade astrocytomas (HGA) by our group and others have uncovered recurrent somatic mutations affecting highly conserved residues in histone 3 (H3) variants. One of these mutations leads to analogous p.Lys27Met (K27M) mutations in both H3.3 and H3.1 variants, is associated with rapid fatal outcome, and occurs specifically in HGA of the midline in children and young adults. This includes diffuse intrinsic pontine gliomas (80 %) and thalamic or spinal HGA (> 90 %), which are surgically challenging locations with often limited tumor material available and critical need for specific histopathological markers. Here, we analyzed formalin-fixed paraffin-embedded tissues from 143 pediatric HGA and 297 other primary brain tumors or normal brain. Immunohistochemical staining for H3K27M was compared to tumor genotype, and also compared to H3 tri-methylated lysine 27 (H3K27me3) staining, previously shown to be drastically decreased in samples carrying this mutation. There was a 100 % concordance between genotype and immunohistochemical analysis of H3K27M in tumor samples. Mutant H3K27M was expressed in the majority of tumor cells, indicating limited intra-tumor heterogeneity for this specific mutation within the limits of our dataset. Both H3.1 and H3.3K27M mutants were recognized by this antibody while non-neoplastic elements, such as endothelial and vascular smooth muscle cells or lymphocytes, did not stain. H3K27me3 immunoreactivity was largely mutually exclusive with H3K27M positivity. These results demonstrate that mutant H3K27M can be specifically identified with high specificity and sensitivity using an H3K27M antibody and immunohistochemistry. Use of this antibody in the clinical setting will prove very useful for diagnosis, especially in the context of small biopsies in challenging midline tumors and will help orient care in the context of the extremely poor prognosis associated with this mutation.

引用

页码：733 / 741

页数：9

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