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

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.
PMID
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Authors

Mayor MeshTerms
Keywords

Cerebrospinal fluid

Diffuse intrinsic pontine glioma (DIPG)

Diffuse midline glioma

H3K27M

Liquid biopsy

Journal Title acta neuropathologica communications
Publication Year Start




PMID- 28416018
OWN - NLM
STAT- MEDLINE
DA  - 20170418
DCOM- 20170420
LR  - 20170421
IS  - 2051-5960 (Electronic)
IS  - 2051-5960 (Linking)
VI  - 5
IP  - 1
DP  - 2017 Apr 17
TI  - Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from
      children with diffuse midline glioma.
PG  - 28
LID - 10.1186/s40478-017-0436-6 [doi]
AB  - 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.
FAU - Huang, Tina Y
AU  - Huang TY
AD  - Department of Neurological Surgery, Northwestern University Feinberg School of
      Medicine, Chicago, IL, USA.
FAU - Piunti, Andrea
AU  - Piunti A
AD  - Department of Biochemistry and Molecular Genetics, Northwestern University
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Lulla, Rishi R
AU  - Lulla RR
AD  - Division of Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation, Ann
      & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
FAU - Qi, Jin
AU  - Qi J
AD  - Department of Neurological Surgery, Northwestern University Feinberg School of
      Medicine, Chicago, IL, USA.
FAU - Horbinski, Craig M
AU  - Horbinski CM
AD  - Department of Neurological Surgery, Northwestern University Feinberg School of
      Medicine, Chicago, IL, USA.
AD  - Department of Pathology, Northwestern University Feinberg School of Medicine,
      Chicago, IL, USA.
FAU - Tomita, Tadanori
AU  - Tomita T
AD  - Division of Pediatric Neurosurgery, Department of Surgery, Ann & Robert H. Lurie 
      Children's Hospital of Chicago, Chicago, IL, USA.
AD  - Department of Neurological Surgery, Northwestern University Feinberg School of
      Medicine, Chicago, IL, USA.
FAU - James, C David
AU  - James CD
AD  - Department of Neurological Surgery, Northwestern University Feinberg School of
      Medicine, Chicago, IL, USA.
AD  - Department of Biochemistry and Molecular Genetics, Northwestern University
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Shilatifard, Ali
AU  - Shilatifard A
AD  - Department of Biochemistry and Molecular Genetics, Northwestern University
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Saratsis, Amanda M
AU  - Saratsis AM
AD  - Division of Pediatric Neurosurgery, Department of Surgery, Ann & Robert H. Lurie 
      Children's Hospital of Chicago, Chicago, IL, USA. [email protected]
AD  - Department of Neurological Surgery, Northwestern University Feinberg School of
      Medicine, Chicago, IL, USA. [email protected]
LA  - eng
PT  - Journal Article
PT  - Validation Studies
DEP - 20170417
PL  - England
TA  - Acta Neuropathol Commun
JT  - Acta neuropathologica communications
JID - 101610673
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DNA, Neoplasm)
RN  - 0 (H3 histone family member 3A, human)
RN  - 0 (HIST1H3B protein, human)
RN  - 0 (Histones)
SB  - IM
MH  - Biomarkers, Tumor/cerebrospinal fluid/genetics
MH  - Brain/metabolism/pathology/surgery
MH  - Brain Neoplasms/cerebrospinal fluid/*genetics/metabolism/surgery
MH  - Cell Line, Tumor
MH  - DNA Mutational Analysis/*methods
MH  - DNA, Neoplasm/*cerebrospinal fluid
MH  - Feasibility Studies
MH  - Glioma/cerebrospinal fluid/*genetics/metabolism/surgery
MH  - Histones/cerebrospinal fluid/*genetics
MH  - Humans
MH  - Immunohistochemistry
MH  - Mutation
PMC - PMC5392913
OTO - NOTNLM
OT  - *Cerebrospinal fluid
OT  - *Diffuse intrinsic pontine glioma (DIPG)
OT  - *Diffuse midline glioma
OT  - *H3K27M
OT  - *Liquid biopsy
EDAT- 2017/04/19 06:00
MHDA- 2017/04/21 06:00
CRDT- 2017/04/19 06:00
PHST- 2017/02/17 [received]
PHST- 2017/04/08 [accepted]
AID - 10.1186/s40478-017-0436-6 [doi]
AID - 10.1186/s40478-017-0436-6 [pii]
PST - epublish
SO  - Acta Neuropathol Commun. 2017 Apr 17;5(1):28. doi: 10.1186/s40478-017-0436-6.

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