Abstract

According to the recently updated World Health Organization (WHO) classification (2016), grade II–III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II–III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II–III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II–III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalJournal of Neuro-Oncology
DOIs
StateAccepted/In press - Apr 18 2017

Fingerprint

Astrocytoma
Glioblastoma
Genome
Methylation
Neoplasms
Epigenomics
Recurrence
Mutation
Genomic Instability
Glioma
Disease-Free Survival
Sequence Analysis
Immunohistochemistry
Control Groups
Survival

Keywords

  • Astrocytoma
  • Glioblastoma
  • IDH mutation
  • Methylation array
  • Rapidly progressing astrocytoma

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Cite this

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title = "Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis",
abstract = "According to the recently updated World Health Organization (WHO) classification (2016), grade II–III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II–III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II–III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II–III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.",
keywords = "Astrocytoma, Glioblastoma, IDH mutation, Methylation array, Rapidly progressing astrocytoma",
author = "Richardson, {Timothy E.} and Matija Snuderl and Jonathan Serrano and Karajannis, {Matthias A.} and Adriana Heguy and Dwight Oliver and Raisanen, {Jack M.} and Maher, {Elizabeth A.} and Edward Pan and Samuel Barnett and Chunyu Cai and Habib, {Amyn A.} and Bachoo, {Robert M.} and Hatanpaa, {Kimmo J.}",
year = "2017",
month = "4",
day = "18",
doi = "10.1007/s11060-017-2431-y",
language = "English (US)",
pages = "1--10",
journal = "Journal of Neuro-Oncology",
issn = "0167-594X",
publisher = "Kluwer Academic Publishers",

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TY - JOUR

T1 - Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas

T2 - a genome-wide analysis

AU - Richardson, Timothy E.

AU - Snuderl, Matija

AU - Serrano, Jonathan

AU - Karajannis, Matthias A.

AU - Heguy, Adriana

AU - Oliver, Dwight

AU - Raisanen, Jack M.

AU - Maher, Elizabeth A.

AU - Pan, Edward

AU - Barnett, Samuel

AU - Cai, Chunyu

AU - Habib, Amyn A.

AU - Bachoo, Robert M.

AU - Hatanpaa, Kimmo J.

PY - 2017/4/18

Y1 - 2017/4/18

N2 - According to the recently updated World Health Organization (WHO) classification (2016), grade II–III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II–III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II–III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II–III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

AB - According to the recently updated World Health Organization (WHO) classification (2016), grade II–III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II–III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16 months and the mean total survival among the three patients who have died during the follow-up was only 31 months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II–III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II–III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

KW - Astrocytoma

KW - Glioblastoma

KW - IDH mutation

KW - Methylation array

KW - Rapidly progressing astrocytoma

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U2 - 10.1007/s11060-017-2431-y

DO - 10.1007/s11060-017-2431-y

M3 - Article

C2 - 28421459

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JO - Journal of Neuro-Oncology

JF - Journal of Neuro-Oncology

SN - 0167-594X

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