Open AccessIntratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma
Author(s) -
Nicole Parker,
Amanda L. Hudson,
Peter Khong,
Jonathan Parkinson,
Trisha Dwight,
Rowan J. Ikin,
Ying Zhu,
Zhangkai J. Cheng,
Fatemeh Vafaee,
Jason Chen,
Helen Wheeler,
Viive M. Howell
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep22477
Subject(s) - temozolomide , epigenetics , dna methylation , biology , dna repair , o 6 methylguanine dna methyltransferase , tumour heterogeneity , genetic heterogeneity , methyltransferase , cancer research , dna mismatch repair , in silico , biomarker , dna damage , methylation , glioblastoma , genetics , bioinformatics , gene , dna , phenotype , cancer , gene expression
Heterogeneity is a hallmark of glioblastoma with intratumoral heterogeneity contributing to variability in responses and resistance to standard treatments. Promoter methylation status of the DNA repair enzyme O 6 -methylguanine DNA methyltransferase (MGMT) is the most important clinical biomarker in glioblastoma, predicting for therapeutic response. However, it does not always correlate with response. This may be due to intratumoral heterogeneity, with a single biopsy unlikely to represent the entire lesion. Aberrations in other DNA repair mechanisms may also contribute. This study investigated intratumoral heterogeneity in multiple glioblastoma tumors with a particular focus on the DNA repair pathways. Transcriptional intratumoral heterogeneity was identified in 40% of cases with variability in MGMT methylation status found in 14% of cases. As well as identifying intratumoral heterogeneity at the transcriptional and epigenetic levels, targeted next generation sequencing identified between 1 and 37 unique sequence variants per specimen. In-silico tools were then able to identify deleterious variants in both the base excision repair and the mismatch repair pathways that may contribute to therapeutic response. As these pathways have roles in temozolomide response, these findings may confound patient management and highlight the importance of assessing multiple tumor biopsies.