Commentary
Chromatin is composed of nucleosomes, with each nucleosome consisting of an octamer of two copies each of histones H3, H4, H2A, and H2B. Chromatin is critical for the control of transcription, replication, DNA repair and other aspects of genomic stability. In humans, there are different histone H3 variants. H3.3 proteins are expressed thoughout the cell cycle as well as in quiescent cells [1], while H3.1 and H3.2 are expressed only during the S-phase [2].
In 2012, recurrent mutations in H3F3A, which encodes histone 3 variant H3.3, were firstly identified in pediatric and young adult high-grade gliomas (HGGs) [3,4]. Subsequent studies have extended the breadth of cancers known to carry mutations in histone H3, including chondroblastoma, giant cell tumors of bone, chondrosarcoma, pediatric soft tissue sarcoma, head and neck squamous cell carcinoma and leukemia [5-8]. In HGGs, H3F3A mutations lead to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/V) involved in key regulatory post-translational modifications. HGGs with H3 K27M mutation almost exclusively occur in midline structures (thalamus, brain stem, or spinal cord) and have been designated as “diffuse midline gliomas (DIPGs), K27M-mutant” in the WHO classification of tumors of the CNS 2016 [9]. Otherwise, HGGs with H3.3 G34R/V mutation have not been defined as a separate entity in the WHO classification 2016.
HGGs with H3.3 G34R/V mutation occur most often in cerebral hemispheres of teenagers and young adults (age 10 to 25 years), with a generally poor prognosis [10-12]. Histologically, these HGGs typically show an undifferentiated phenotype with a small blue-cell component, a glioblastoma-like astrocytic component or a mixture of the two. Therefore, they have been diagnosed as glioblastoma (GBM) or primitive neuroepithelial tumor (PNET) in the past [10,13]. One case of astroblastoma [14] and two cases of neuro-epithelial tumors containing glial and dysplastic ganglion cell components [15] with H3.3 G34 mutation have been reported. We know that the histological spectrum of mutations associated with tumor entities is often wider than initially described. For example the list of brain tumors with BRAF-V600E is growing [16]. Hence, the morphologic spectrum of brain tumors with H3.3 G34 mutation may further extend in future studies. Maybe these tumors should be defined as neuro-epithelial tumors with H3.3 G34 mutation.
H3F3A encoding histone H3.3 is mutated at high frequency in pediatric brain and bone tumors. These H3F3A missense mutations affect three amino acids on the N-terminus of H3.3, K27, G34 and K36. K27 and K36 are mutated to methilnine (M) in pediatric DIPGs and chondroblastoma respectively [3,4,17]. G34 mutated to various amino acids, including arginine (R) and valine (V) in pediatric HGGs and tryptophan (W) and leucine (L) in giant cell tumors of the bone (GCTB) [5]. The K27M mutant competes for binding to EZH2, the H3K27-specific lysine methyltransferase (KMT), and thus effectively sequesters EZH2 and the PRC2 complex to prevent it from further propagating the repressive H3K27 methylation mark [18,19]. The K36M mutant inhibits KMTs specific to H3K36, including NSD1, NSD2 and SETD2 and reduces global H3K36 methylation [7,20]. It suggest that the lysine-to-methionine mutations inhibit H3 methylation pathways to promote tumorigenesis.
Somatic mutations at G34 in H3F3A were first identified in pediatric HGGs of the cerebral cortex. And the cortical pediatric HGGs bear a more common G34R mutation than G34V mutation [21]. G34 lies towards the base of the H3 tail, close to the DNA entry and exit points of the nucleosome. G34 sits just 2 residues away from K36 and 4 residues from P38, a residue that can adopt distinct conformations to control K36 methylation [22]. G34R and V mutants have been investigated to diminish H3K36me2/3 in cis on the same histone H3 tail, but exhibit no dominant effect to block K36 methylation on WT H3 tails [23].
HGGs bearing G34R/V mutations are also frequently mutated for ATRX (α-thalassaemia/mental retardation syndrome X-linked), DAXX (death-domain associated protein) and TP53 [3,24]. In addition, MGMT promoter methylation is frequently detected in G34-mutant HGGs(74%) and associated with a significantly better prognosis [10]. G34-mutant HGGs also display 2q loss (67%), 4q loss (70%), PDGFRA amplications (27%), CDNK2A detetion (14%) and CDK6 amplification (10%) [10,25,26]. H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene that is causative of GBMs [27].
In conclusion, HGGs with H3.3 G34 mutations are restricted in cerebral cortex of adolescence or young adulthood. These tumors display a divergent histopahtologic apperance, including GBM-like and PNET-like morphology. Glial and dysplastic ganglion cell components can also been found. Except the G34 mutation, other molecular features in G34-mutant HGGs include ATRX and TP53 mutations, MGMT promoter methylation. However, how the G34 mutants exert dominant effects on histone H3 biology, remains unknown, which provides a novel avenue for targeted therapy in these HGGs.
References
2. Osley MA. The regulation of histone synthesis in the cell cycle. Annual Review of Biochemistry. 1991 Jul;60(1):827- 61.
3. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, et al. Driver mutations in histone H3. 3 and chromatin remodelling genes in paediatric glioblastoma. Nature. 2012 Feb;482(7384):226-31.
4. Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genetics. 2012 Mar;44(3):251-53.
5. Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nature Genetics. 2013 Dec;45(12):1479-82.
6. McManus IC, Richards P. Choice and ordering of medical school applications: cause for concern. The Lancet. 1987 Jul 4;330(8549):33-5.
7. Lu C, Jain SU, Hoelper D, Bechet D, Molden RC, Ran L, et al. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science. 2016 May 13;352(6287):844-9.
8. Papillon-Cavanagh S, Lu C, Gayden T, Mikael LG, Bechet D, Karamboulas C, et al. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nature Genetics. 2017 Feb;49(2):180-5.
9. Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathologica. 2016 Jun 1;131(6):803-20.
10. Korshunov A, Capper D, Reuss D, Schrimpf D, Ryzhova M, Hovestadt V, et al. Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathologica. 2016 Jan 1;131(1):137-46.
11. Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, et al. Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2018 Feb;36(10):951-958.
12. Sturm D, Pfister SM, Jones DT. Pediatric gliomas: current concepts on diagnosis, biology, and clinical management. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2017 Jul 20;35(21):2370-7.
13. Gessi M, Gielen GH, Hammes J, Dörner E, Zur Mühlen A, Waha A, et al. H3. 3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications?. Journal of Neuro-oncology. 2013 Mar 1;112(1):67-72.
14. Yoshimoto K, Hatae R, Sangatsuda Y, Suzuki SO, Hata N, Akagi Y, et al. Prevalence and clinicopathological features of H3. 3 G34-mutant high-grade gliomas: a retrospective study of 411 consecutive glioma cases in a single institution. Brain Tumor Pathology. 2017 Jul 1;34(3):103-12.
15. Andreiuolo F, Lisner T, Zlocha J, Kramm C, Koch A, Bison B, et al. H3F3A-G34R mutant high grade neuroepithelial neoplasms with glial and dysplastic ganglion cell components. Acta Neuropathologica Communications. 2019 Dec;7(1):78.
16. Kristensen BW, Priesterbach-Ackley LP, Petersen JK, Wesseling P. Molecular pathology of tumors of the central nervous system. Annals of Oncology. 2019 Aug 1;30(8):1265-78.
17. Fang D, Gan H, Lee JH, Han J, Wang Z, Riester SM, et al. The histone H3. 3K36M mutation reprograms the epigenome of chondroblastomas. Science. 2016 Jun 10;352(6291):1344-8.
18. Lewis PW, Müller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science. 2013 May 17;340(6134):857-61.
19. Fang D, Gan H, Cheng L, Lee JH, Zhou H, Sarkaria JN, et al. H3. 3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers. Elife. 2018 Jun 22;7:e36696.
20. Yang S, Zheng X, Lu C, Li GM, Allis CD, Li H. Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. Genes & Development. 2016 Jul 15;30(14):1611-6.
21. Kallappagoudar S, Yadav RK, Lowe BR, Partridge JF. Histone H3 mutations—a special role for H3. 3 in tumorigenesis?. Chromosoma. 2015 Jun 1;124(2):177-89.
22. Nelson CJ, Santos-Rosa H, Kouzarides T. Proline isomerization of histone H3 regulates lysine methylation and gene expression. Cell. 2006 Sep 8;126(5):905-16.
23. Shi L, Shi J, Shi X, Li W, Wen H. Histone H3. 3 G34 mutations alter histone H3K36 and H3K27 methylation in cis. Journal of Molecular Biology. 2018 May 25;430(11):1562-5.
24. Lindroth AM, Park YJ, Matía V, Squatrito M. The mechanistic GEMMs of oncogenic histones. Human Molecular Genetics. 2020 Jul 8.
25. Rodriguez FJ, Vizcaino MA, Lin MT. Recent advances on the molecular pathology of glial neoplasms in children and adults. The Journal of Molecular Diagnostics. 2016 Sep 1;18(5):620-34.
26. Vettermann FJ, Felsberg J, Reifenberger G, Hasselblatt M, Forbrig R, Berding G, et al. Characterization of diffuse gliomas with histone H3-G34 mutation by MRI and dynamic 18F-FET PET. Clinical Nuclear Medicine. 2018 Dec 1;43(12):895-8.
27. Bjerke L, Mackay A, Nandhabalan M, Burford A, Jury A, Popov S, et al. Histone H3. 3 mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discovery. 2013 May 1;3(5):512-9.