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Sci Rep. 2016 Mar 4;6:22477. doi: 10.1038/srep22477.

Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.

Parker NR1,2,3, Hudson AL1,2,3, Khong P1,2,3, Parkinson JF1,2,3, Dwight T4,2,3, Ikin RJ1,2,3, Zhu Y2,3,5, Cheng ZJ6,7, Vafaee F7,8, Chen J9, Wheeler HR1,2,3, Howell VM1,2,3.

Author information

Sydney Neuro-Oncology Group, Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, Australia, 2065.
Northern Sydney Local Health District, St Leonards, NSW, Australia, 2065.
Sydney Medical School Northern, University of Sydney, NSW, Australia, 2065.
Cancer Genetics, Hormones and Cancer Group, Kolling Institute, St Leonards, Australia, 2065.
Hunter New England Health, NSW, Australia, 2305.
Department of Physics, University of Sydney, NSW, Australia, 2006.
Charles Perkins Centre, University of Sydney, NSW, Australia, 2006.
School of Mathematics and Statistics, University of Sydney, NSW, Australia, 2006.
Department of Anatomical Pathology, Northern Sydney Local Health District, St Leonards, NSW, Australia, 2065.


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.

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