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.
N1 - Publisher Copyright:
© 2017, Springer Science+Business Media New York.
PY - 2017/5/1
Y1 - 2017/5/1
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
AN - SCOPUS:85017591643
SN - 0167-594X
VL - 133
SP - 183
EP - 192
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
IS - 1
ER -