HR A systematic review on the current radiogenomics studies in glioblastomas, p. 32-44 J VOLUME 4 | ISSUE 3 Review Neuro/Head and Neck Radiology A systematic review on the current radiogenomics studies in glioblastomas Sotirios Bisdas1,2, Evangelia Ioannidou1,3, Felice D’Arco4 1Department of Neuroradiology, The National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, London, UK. 2Department of Brain Repair and Rehabilitation, Institute of Neurology, University College London, London, UK 3Medical School, University of Ioannina, Ioannina, Greece 4Neuroradiology Section, Department of Radiology, Great Ormond Street Hospital for Children, London, UK Submission: 19/3/2019 | Acceptance: 26/08/2019 Abstract Glioblastomas (GBM) have one of the poorest progno- rived from both morphologic and functional imaging ses of any cancer. Current cutting-edge research aims biomarkers (radiomics) in brain. Radiogenomics is at- to pave the way for new non-invasive methods of di- tempting to probe any correlation between radiological agnosing brain tumours through innovative imaging and histological features and hopefully assess the phys- techniques and genomic information from tumour sam- iological heterogeneity and genetic alterations paving ples. Over the past few years, various whole genome se- the way to a holistic approach of the tumour metabol- quencing analysis has identified biomarkers and thus ic, pathophysiological and structural fingerprint. This gradually changed the way of diagnosing brain tu- systematic review aims to summarise the current pub- mours. In this context, MRI is a versatile imaging tech- lished evidence of radiogenomics in GBM and also raise nique as it can provide multifaceted information de- awareness for future research in this field. Key words Glioblastoma; Radiomics; Genomics; Biomarkers; Review; MR imaging Corresponding Professor Sotirios Bisdas Author, Department of Neuroradiology, The National Hospital for Neurology and Guarantor Neurosurgery, Box 65, Queen Square 8-11, London WC1N 3BG, United Kingdom, Email: [email protected] 32 A systematic review on the current radiogenomics studies in glioblastomas, p. 32-44 HR VOLUME 4 | ISSUE 3 J Introduction H3F3A gene, causing the encoding of histone H3.3; (v) A remarkable leap in the last decade has been the de- Phosphate and tensin homolog deleted on chromosome velopment of imaging techniques that help distinguish ten (PTEN) gene, also termed MMAC1 or TEP1, on chro- tumour from treatment effect, different tumoural mosomal band 10q23; (vi) Aberrant EGFR activity, re- grade and even different molecular profile. Radiom- sulting in EGFR overexpression; (vii) Receptor CX3CR1 ics is an emerging field that aims to extract quantita- and chemokine CX3CL1 positivity; (viii) O6-methylgua- tive data from medical images in order to characterise nine DNA methyltransferase (MGMT); and (ix) Vascular pathological processes [1]. Radiogenomics (aka imag- Endothelial Growth Factor (VEGF) overexpression. The ing genomics) in neuro-oncology uses radiomics to find role of the aformentioned molecular variations is two- correlation between images and molecular profile of fold. In addition to their use in categorising the large the tumour. Glioblastomas (GBM) manifest strong phe- variety of the glial tumours and contributing to a more notypic variations that can be assessed using magnetic holistic understanding of the pathophysiology and ma- resonance imaging (MRI), but still the majority of their lignant process, they are the foundation of “molecular- underlying biological drivers and genetic aberrations ly targeted therapy” and future of break-through imag- are largely unknown. Thus, efforts have been made ing techniques. over the past years to establish the role of radiogenom- Radiogenomics describes the correlation between ics in GBM as an important goal of this approach is the specific imaging phenotypes, using quantitative data ability to provide personalised therapy. This review and molecular characteristics of a certain disease. This aims to describe the current evidence for the added val- area is setting a new direction in oncology research. ue of radiogenomics in diagnosis and treating GBM and The question that subsequently emerges and we sought outline the premises of this emerging field in the future to address is to which extent are radiogenomics cur- of neuroradiology and neurooncology. rently elucidated. GBM are aggressive malignant primary tumours of the central nervous system (grade IV according to the Material and Methods WHO classification). They account for 45% of malignant Comprehensive, structured literature search was con- primary brain tumours [2]. Over 90% of diagnosed GBM ducted in PubMed for English articles published from cases are primary gliomas, arising from normal glial 2007 to 2018 on radiogenomics in oncology with search cells through multistep oncogenesis. The remaining terms including “radiogenomics”, “imaging genomics”, 10% are secondary gliomas originating from tumours “glioblastoma”, “genomics“, “gene” and “molecular”. of lower grade [3-6]. The aetiological background of Robust inclusion/exclusion criteria were applied for se- GBM has not been fully clarified, however the major- lection of eligible articles. Two authors separately per- ity of them are believed to be of spontaneous origin. formed quality assessment according to the QUADAS-2 The breakthrough in genetic identification in GBM was tool. Data were extracted in a pre-designed spread- achieved by Verhaak et al. [7], who distinguished four sheet following the PRISMA flowchart. References of different molecular subtypes in accordance with the included articles and literature reviews were checked genetic aberrations variability and gene-expression: for additional eligible studies. The principal aim was the classical, mesenchymal, proneural and neural sub- to include original and prevailing studies in humans type. The exact classification of GBMs is indeed very shedding light on the current position of radiogenom- challenging and clearly illustrates the need for new im- ics in the field of neurooncology and especially in GBM. aging surrogates of the molecular profile [8]. Although Studies appraising post-radiation-therapy imaging dis- extensive research has been ongoing for many years, tinctions as well as studies performing radiogenetics new GBM molecular biomarkers are discovered almost using immunochemistry were excluded, as this scope daily. These include: (i) Loss of 1p, 19q and 10q hete- of radiation genomics is clearly outside of our ongoing rozygosity; (ii) IDH1 or IDH2 mutations [9]; (iii) Elevated research and interest field. Furthermore, literature re- expression of epidermal growth factor (EGF), Iatrophi- ferring only to the term “radiomics”, without any el- lin, and "7-transmembrane domain-containing" pro- ements of “radiogenomics”, were not included in our tein 1 on chromosome 1 (ELTD1); (iv) Mutation in the review. In total, we included 23 articles, which con- 33 HR A systematic review on the current radiogenomics studies in glioblastomas, p. 32-44 J VOLUME 4 | ISSUE 3 tained original research into the current role of radiog- the images into standard stereotactic atlas space. enomics in GBM. The summary, including the unique The first comprehensive radiogenomic paper using value and any major shortcomings of the eligible stud- the open-access TCGA data base and TCIA images was ies are presented below. Illustrative examples of basic published by Zinn et al. [11]. Their analysis aimed to ex- radiogenomics correlation tasks for GBM genotypes plore genomic correlates of invasion and volume of the classification using multimodal MRI and the respective tumour. Peritumoural FLAIR and T2-weighted(w) im- textural features are shown in Figs. 1-4, where texture age signals were used to evaluate the extent of oedema images (intensities of the neighbouring voxels) are gen- and tumour infiltration, subgrouping the patients into erated using ITK-SNAP (http://itksnap.org). Compre- high, medium, and low FLAIR volume groups. High and hensive biomarker extraction can be performed using low groups were analysed and compared for differen- shape and intensity features, to capture tumour shape tial genomic expression profiles. The top upregulated or for distribution mapping through all voxels in the gene in the discovery (4-fold upregulation) and valida- segmented tumours. Haralick texture features relate tion (11-fold) sets was perostin (POSTN). The top down- to the tumour texture and include angular secondary regulated microRNA in both sets was miR-219, which moment, image contrast (large differences between binds and negatively regulates POSTN. Above median neighbouring voxels), entropy (the orderliness of the expression of POSTN resulted in significantly decreased gray level distribution in the image), correlation, sum survival and shorter time to disease progression. High square, sum average, inverse difference moment, sum POSTN and low miR-219 expression were significantly entropy, difference variance, sum variance, difference associated with the mesenchymal GBM subtype. How- entropy. ever, a limitation in the TCGA radiological data is the lack of image-tissue sample registration; thus, gene Results expression profiles cannot be matched to a specific The included studies and the investigated radiomics location on MRI [11]. Moreover, due to the large num- and genomics features along with any additional im- ber of probes, false positive gene hits may occur.