title: Intratumoral heterogeneity identified at the epigenetic, genetic and transcriptional level in glioblastoma.
abstract: 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.
authors.affiliation: 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.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Parker
authors.affiliation: 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.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Hudson
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Khong
authors.affiliation: 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.
authors.forename: Jonathon F
authors.initials: JF
authors.lastname: Parkinson
authors.affiliation: Cancer Genetics, Hormones and Cancer Group, Kolling Institute, St Leonards, Australia, 2065.|Northern Sydney Local Health District, St Leonards, NSW, Australia, 2065.|Sydney Medical School Northern, University of Sydney, NSW, Australia, 2065.
authors.forename: Trisha
authors.initials: T
authors.lastname: Dwight
authors.affiliation: 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.
authors.forename: Rowan J
authors.initials: RJ
authors.lastname: Ikin
authors.affiliation: Northern Sydney Local Health District, St Leonards, NSW, Australia, 2065.|Sydney Medical School Northern, University of Sydney, NSW, Australia, 2065.|Hunter New England Health, NSW, Australia, 2305.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Physics, University of Sydney, NSW, Australia, 2006.|Charles Perkins Centre, University of Sydney, NSW, Australia, 2006.
authors.forename: Zhangkai Jason
authors.initials: ZJ
authors.lastname: Cheng
authors.affiliation: Charles Perkins Centre, University of Sydney, NSW, Australia, 2006.|School of Mathematics and Statistics, University of Sydney, NSW, Australia, 2006.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Vafaee
authors.affiliation: Department of Anatomical Pathology, Northern Sydney Local Health District, St Leonards, NSW, Australia, 2065.
authors.forename: Jason
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Wheeler
authors.affiliation: 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.
authors.forename: Viive M
authors.initials: VM
authors.lastname: Howell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide