Molecular Imaging in Genomic Medicine

Abstract

Molecular imaging is the result of advances in the fields of molecular biology and imaging technology and has become an increasingly important tool in the discovery and understanding of a wide range of pathophysiologic processes, ranging from genetic disorders to malignant conditions. The advancement in molecular pathology techniques has enabled us to study the complex genotype of disease entities and how it impacts their behaviour and natural history. Image‐guided genomic medicine utilises methodologies to integrate genomic and radiologic data to develop insights into the genotype–phenotype relationship, which in turn can guide medical decision‐making and treatment planning.

Key Concepts

  • Molecular imaging comprises the visualisation, characterisation and measurement of biological processes at the molecular and cellular levels, which can synergise with genomic medicine to enhance our understanding of disease processes.
  • Reporter gene imaging entails encoding proteins that can be rapidly and sensitively assayed as surrogate markers when fused with regulatory regions of the gene of interest as a means of indirectly monitoring molecular basis of diseases.
  • Optical imaging is based on the principle of detecting light in living organisms that reflect molecular processes; types include bioluminescence and fluorescence imaging.
  • ImmunoPET is based on combining the PET with monoclonal antibodies raised against a tumoural antigen.
  • Functional MRI uses the MRI technology to provide a means of measuring brain activity by detecting changes associated with blood flow as a phenotype that can be correlated with genotypic data.
  • Radiomics/imaging genomics leverage machine learning technology to process large data sets acquired through imaging and genomic biomarker extraction and provide valuable insights into pathophysiology and personalised disease management.
  • Gene therapeutics is another area where molecular imaging can be valuable in therapy monitoring and response assessment.

Keywords: molecular; imaging; genomic; reporter; gene; PET; MRI; optical

Figure 1. MicroPET and optical imaging: A side‐to‐side comparison of microPET (FHBG) and optical imaging (Firefly luciferase bioluminescence) in the imaging source of signal at depth below 1 cm from the exterior. Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine (Massoud, T. F., Paulmurugan, R., & Gambhir, S. S. (2010). A molecularly engineered split reporter for imaging protein‐protein interactions with positron emission tomography. Nature Medicine, 16(8), 921–926), copyright (2010).
Figure 2. Optical imaging: PSA luc transgenic mice, with prostate cancer expressing luciferase. (a) Imaging of bioluminescence showing the prostate tumour signal. (b) Same mice using AngioSense 680 EX a near‐infrared labelled fluorescent macromolecule to demonstrate high tumour vascularisation. (c) Image using PET‐CT with 18F FDG (markers over the prostate tumour). Image produced by Francisca Mulero.
Figure 3. ImmunoPET: Coronal whole body PET‐CT imaging 24 h after injection of specific Ab (LEM 2/15) radiolabelled with 89Zr against Antigen MT1‐MMP in mice bearing MT1‐MMP positive pancreatic ductal adenocarcinoma (PDA) cells (red arrow) and MT1‐MMP negative breast cancer cells (yellow arrow). Observe the very high uptake in the PDA tumour showing the higher specificity of the labelled Ab (red arrow) compared with breast cancer with lower expression. Image produced by Francisca Mulero.
Figure 4. fMRI: Discovery and replication fMRI results. (a) First sample: significant clusters associated with the positive slope of polygenic coexpression index (PCI), (b) second sample: scatter plots of percentage signal change in two clusters with significant positive correlation with the PCI in the second sample. Reprinted from DRD2 co‐expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia, Bertolini et al. Translational Psychiatry (2017) 7, e1006.
Figure 5. Imaging genomics: Schema of genome‐association scanning using single‐nucleotide polymorphisms (SNPs) used for phenotypic‐genomic correlation for schizophrenia. Reprinted from DRD2 co‐expression network and a related polygenic index predict imaging, behavioral and clinical phenotypes linked to schizophrenia, Bertolini et al. Translational Psychiatry (2017) 7, e1007.
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Further Reading

Celso L and de Cruz H (2014) Genetic Patterns in Neuroimaging: An Issue of Neuroimaging Clinics. Elsevier Health Sciences. ISBM 0323354637.

Gambhir S and Yaghoubi S (2010) Molecular Imaging with Reporter Genes, 1st edn. Cambridge University Press. ISBN 0521882338.

Kumar D and Eng C (2014) Genomic Medicine: Principles & Practice, 2nd edn. Oxford University Press. ISBN 019989602X.

Long N and Wong W‐T (2014) The Chemistry of Molecular imaging. Wiley. ISBN 978-1-118-09327-6.

Martí‐Bonmatí L and Alberich‐Bayarri A (2016) Imaging Biomarkers: Development and Clinical Integration. Springer. ISBN 3319435043.

Huettel S, Song A and McCarthy G (2014) Functional Magnetic Resonance Imaging, 3rd edn. Sinauer Associates, Inc. ISBN 0878936270.

Weissleder R (2010) Molecular Imaging: Principles & Practice. PMPH‐USA. ISBN 1607950057.

Zheng L and Shameem M (2015) Monoclonal Antibodies: Development, Delivery and Applications. Future Science Ltd., John Hopkins School of Medicine, USA & Merck, USA. ISBN 9781910419472.

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Shaikh, Faiq A, Mulero, Francisca, and Mohiuddin, Sohaib A(Jul 2017) Molecular Imaging in Genomic Medicine. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027219]