Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2017

Open Access 01-12-2017 | Research

Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma

Authors: Tina Y. Huang, Andrea Piunti, Rishi R. Lulla, Jin Qi, Craig M. Horbinski, Tadanori Tomita, C. David James, Ali Shilatifard, Amanda M. Saratsis

Published in: Acta Neuropathologica Communications | Issue 1/2017

Login to get access

Abstract

Diffuse midline gliomas (including diffuse intrinsic pontine glioma, DIPG) are highly morbid glial neoplasms of the thalamus or brainstem that typically arise in young children and are not surgically resectable. These tumors are characterized by a high rate of histone H3 mutation, resulting in replacement of lysine 27 with methionine (K27M) in genes encoding H3 variants H3.3 (H3F3A) and H3.1 (HIST1H3B). Detection of these gain-of-function mutations has clinical utility, as they are associated with distinct tumor biology and clinical outcomes. Given the paucity of tumor tissue available for molecular analysis and relative morbidity of midline tumor biopsy, CSF-derived tumor DNA from patients with diffuse midline glioma may serve as a viable alternative for clinical detection of histone H3 mutation. We demonstrate the feasibility of two strategies to detect H3 mutations in CSF-derived tumor DNA from children with brain tumors (n = 11) via either targeted Sanger sequencing of H3F3A and HIST1H3B, or H3F3A c.83 A > T detection via nested PCR with mutation-specific primers. Of the six CSF specimens from children with diffuse midline glioma in our cohort, tumor DNA sufficient in quantity and quality for analysis was isolated from five (83%), with H3.3K27M detected in four (66.7%). In addition, H3.3G34V was identified in tumor DNA from a patient with supratentorial glioblastoma. Test sensitivity (87.5%) and specificity (100%) was validated via immunohistochemical staining and Sanger sequencing in available matched tumor tissue specimens (n = 8). Our results indicate that histone H3 gene mutation is detectable in CSF-derived tumor DNA from children with brain tumors, including diffuse midline glioma, and suggest the feasibility of “liquid biopsy” in lieu of, or to complement, tissue diagnosis, which may prove valuable for stratification to targeted therapies and monitoring treatment response.
Appendix
Available only for authorised users
Literature
1.
Bartram A, Poon C, Neufeld J (2009) Nucleic acid contamination of glycogen used in nucleic acid precipitation and assessment of linear polyacrylamide as an alternative co-precipitant. Biotechniques 47:1019–1022CrossRefPubMed
2.
Buczkowicz P, Hoeman C, Rakopoulos P, Pajovic S, Letourneau L, Dzamba M, Morrison A, Lewis P, Bouffet E, Bartels U et al (2014) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451–456CrossRefPubMedPubMedCentral
3.
Castel D, Philippe C, Calmon R, Le Dret L, Truffaux N, Boddaert N, Pages M, Taylor KR, Saulnier P, Lacroix L et al (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827CrossRefPubMedPubMedCentral
4.
Ciobanu MC, Burgaud G, Dufresne A, Breuker A, Redou V, Ben Maamar S, Gaboyer F, Vandenabeele-Trambouze O, Lipp JS, Schippers A et al (2014) Microorganisms persist at record depths in the subseafloor of the Canterbury Basin. ISME J 8:1370–1380CrossRefPubMedPubMedCentral
5.
De Mattos-Arruda L, Mayor R, Ng CK, Weigelt B, Martinez-Ricarte F, Torrejon D, Oliveira M, Arias A, Raventos C, Tang J et al (2015) Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun 6:8839CrossRefPubMed
6.
Dohm JC, Lottaz C, Borodina T, Himmelbauer H (2008) Substantial biases in ultra-short read data sets from high-throughput DNA sequencing. Nucleic Acids Res 36:e105CrossRefPubMedPubMedCentral
7.
Fanelli M, Amatori S, Barozzi I, Minucci S (2011) Chromatin immunoprecipitation and high-throughput sequencing from paraffin-embedded pathology tissue. Nat Protoc 6:1905–1919CrossRefPubMed
8.
Feng J, Hao S, Pan C, Wang Y, Wu Z, Zhang J, Yan H, Zhang L, Wan H (2015) The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 46:1626–1632CrossRefPubMed
9.
10.
Gielen GH, Gessi M, Hammes J, Kramm CM, Waha A, Pietsch T (2013) H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas. Am J Clin Pathol 139:345–349CrossRefPubMed
11.
Grasso CS, Tang Y, Truffaux N, Berlow NE, Liu L, Debily MA, Quist MJ, Davis LE, Huang EC, Woo PJ et al (2015) Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 21:555–559CrossRefPubMedPubMedCentral
12.
Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, Fang D, Huang X, Tom MW, Ngo V et al (2014) Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20:1394–1396CrossRefPubMedPubMedCentral
13.
14.
Hoffman LM, DeWire M, Ryall S, Buczkowicz P, Leach J, Miles L, Ramani A, Brudno M, Kumar SS, Drissi R et al (2016) Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 4:1CrossRefPubMedPubMedCentral
15.
Jones C, Karajannis MA, Jones DT, Kieran MW, Monje M, Baker SJ, Becher OJ, Cho YJ, Gupta N, Hawkins C, et al (2016) Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol
16.
Khuong-Quang DA, Buczkowicz P, Rakopoulos P, Liu XY, Fontebasso AM, Bouffet E, Bartels U, Albrecht S, Schwartzentruber J, Letourneau L et al (2012) K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124:439–447CrossRefPubMedPubMedCentral
17.
Kieran MW, Goumnerova LC, Prados M, Gupta N (2016) Biopsy for diffuse intrinsic pontine glioma: a reappraisal. J Neurosurg Pediatr 18:390–391CrossRefPubMed
18.
Lewis PW, Muller MM, Koletsky MS, Cordero F, Lin S, Banaszynski LA, Garcia BA, Muir TW, Becher OJ, Allis CD (2013) Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340:857–861CrossRefPubMedPubMedCentral
19.
Li Y, Pan W, Connolly ID, Reddy S, Nagpal S, Quake S, Gephart MH (2016) Tumor DNA in cerebral spinal fluid reflects clinical course in a patient with melanoma leptomeningeal brain metastases. J Neurooncol 128:93–100CrossRefPubMed
20.
21.
Malboeuf CM, Yang X, Charlebois P, Qu J, Berlin AM, Casali M, Pesko KN, Boutwell CL, DeVincenzo JP, Ebel GD et al (2013) Complete viral RNA genome sequencing of ultra-low copy samples by sequence-independent amplification. Nucleic Acids Res 41:e13CrossRefPubMed
22.
Mueller S, Hashizume R, Yang X, Kolkowitz I, Olow AK, Phillips J, Smirnov I, Tom MW, Prados MD, James CD et al (2014) Targeting Wee1 for the treatment of pediatric high-grade gliomas. Neuro Oncol 16:352–360CrossRefPubMed
23.
Nikbakht H, Panditharatna E, Mikael LG, Li R, Gayden T, Osmond M, Ho CY, Kambhampati M, Hwang EI, Faury D et al (2016) Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat Commun 7:11185CrossRefPubMedPubMedCentral
24.
Nikiforova MN, Wald AI, Melan MA, Roy S, Zhong S, Hamilton RL, Lieberman FS, Drappatz J, Amankulor NM, Pollack IF et al (2016) Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. Neuro Oncol 18:379–387CrossRefPubMed
25.
Pan W, Gu W, Nagpal S, Gephart MH, Quake SR (2015) Brain tumor mutations detected in cerebral spinal fluid. Clin Chem 61:514–522CrossRefPubMed
26.
Pentsova EI, Shah RH, Tang J, Boire A, You D, Briggs S, Omuro A, Lin X, Fleisher M, Grommes C et al (2016) Evaluating cancer of the central nervous system through next-generation sequencing of cerebrospinal fluid. J Clin Oncol 34:2404–2415CrossRefPubMed
27.
Piunti A, Hashizume R, Morgan MA, Bartom ET, Horbinski CM, Marshall SA, Rendleman EJ, Ma Q, Takahashi YH, Woodfin AR, et al (2017) Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med
28.
Piunti A, Shilatifard A (2016) Epigenetic balance of gene expression by Polycomb and COMPASS families. Science 352:aad9780CrossRefPubMed
29.
Polivka J Jr, Pesta M, Janku F (2015) Testing for oncogenic molecular aberrations in cell-free DNA-based liquid biopsies in the clinic: are we there yet? Expert Rev Mol Diagn 15:1631–1644. PMID: 26559503CrossRefPubMedPubMedCentral
30.
Puget S, Beccaria K, Blauwblomme T, Roujeau T, James S, Grill J, Zerah M, Varlet P, Sainte-Rose C (2015) Biopsy in a series of 130 pediatric diffuse intrinsic Pontine gliomas. Childs Nerv Syst 31:1773–1780CrossRefPubMed
31.
Saratsis AM, Kambhampati M, Snyder K, Yadavilli S, Devaney JM, Harmon B, Hall J, Raabe EH, An P, Weingart M et al (2014) Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes. Acta Neuropathol 127:881–895CrossRefPubMed
32.
Saratsis AM, Yadavilli S, Magge S, Rood BR, Perez J, Hill DA, Hwang E, Kilburn L, Packer RJ, Nazarian J (2012) Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid. Neuro Oncol 14:547–560CrossRefPubMed
33.
Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M et al (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231CrossRefPubMed
34.
Shingyoji M, Kageyama H, Sakaida T, Nakajima T, Matsui Y, Itakura M, Iuchi T, Yokoi S, Kimura H, Iizasa T (2011) Detection of epithelial growth factor receptor mutations in cerebrospinal fluid from patients with lung adenocarcinoma suspected of neoplastic meningitis. J Thorac Oncol 6:1215–1220CrossRefPubMed
35.
Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT, Heguy A, Santi M, Thompson CB, Judkins AR (2013) Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol 23:558–564CrossRefPubMed
36.
Walker DA, Liu J, Kieran M, Jabado N, Picton S, Packer R, St Rose C, Group CPNPCC (2013) A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro Oncol 15:462–468CrossRefPubMedPubMedCentral
37.
Wang Y, Springer S, Zhang M, McMahon KW, Kinde I, Dobbyn L, Ptak J, Brem H, Chaichana K, Gallia GL et al (2015) Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci U S A 112:9704–9709CrossRefPubMedPubMedCentral
38.
Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M et al (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253CrossRefPubMedPubMedCentral
39.
Zhang R, Han J, Daniels D, Huang H, Zhang Z (2016) Detecting the H3F3A mutant allele found in high-grade pediatric glioma by real-time PCR. J Neurooncol 126:27–36CrossRefPubMed
Metadata
Title
Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma
Authors
Tina Y. Huang
Andrea Piunti
Rishi R. Lulla
Jin Qi
Craig M. Horbinski
Tadanori Tomita
C. David James
Ali Shilatifard
Amanda M. Saratsis
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2017
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/s40478-017-0436-6

Other articles of this Issue 1/2017

Acta Neuropathologica Communications 1/2017 Go to the issue

Research

A data-driven approach links microglia to pathology and prognosis in amyotrophic lateral sclerosis

Retraction Note

Retraction Note: Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype

Research

The frequency and prognostic effect of TERT promoter mutation in diffuse gliomas

Research

Rho-associated protein kinase 2 (ROCK2): a new target of autoimmunity in paraneoplastic encephalitis

Research

Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease

Research

Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons