Dr Gareth Bond

Dr Gareth Bond

Institute of Cancer and Genomic Sciences
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Contact details

Email
g.bond.1@bham.ac.uk
Address
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

There is great heterogeneity among individuals in their risk of developing cancer, their disease progression and their responses to therapy.  This heterogeneity is a major obstacle in designing uniformly effective prevention, screening and treatment strategies and motivates the large effort to personalize these interventions. Both rare and common inherited genetic variants have great potential to help us better understand human cancer and to serve as important biomarkers in the clinic. Genome-wide association studies (GWASs) have identified hundreds of commonly inherited single nucleotide polymorphisms (SNPs) significantly associated with allelic differences in cancer susceptibility. Whole genome sequencing of cancer patients is identifying hundreds of rare novel potential pathogenic variants. Despite these findings, major challenges remain in translating these associations into clinical applications.

My laboratory aims to improve the understanding and management of cancer heterogeneity with inherited genetic information, using a combination of computational, epidemiological and experimental techniques. During the course of our work we have been focusing on developing and executing studies to determine genotype-phenotype relationships from large, human genotype and sequencing databases. We aim to include both computational and experimental biologists, as well as functional genomic and molecular techniques in order test causalities behind associations and to incorporate genetic findings into new drug treatment regimes.

Our overarching aims are to:

  • Identify and characterize causal, functional inherited genetic variants in genes within well-defined signaling pathways that affect human cancer.
  • Use identified variants to address fundamental questions about human cancer and evolution.
  • Use biological knowledge of the variants to maximize their clinical utility.

Qualifications

  • Postdoctoral, Institute for Advanced Study, Princeton, New Jersey, USA.    
  • Postdoctoral Associate of Professor Arnold J. Levine, The Rockefeller University, New York, New York, USA.
  • PhD in Biology, Columbia University, Department of Biological Sciences, New York, New York, USA.

Biography

We have begun our work in the well-defined p53 tumour suppressor network: a good model system to begin to assess the potential impact of SNPs on cancer for many reasons.  Other genetic variations in the pathway, such as low-frequency inherited mutations and common somatic mutations, are already used as critical biomarkers in patient-stratification strategies in the clinic, which can help both to inform our studies and to serve as a point of integration.  Moreover, these genetic variations have been shown to affect cancer risk, progression and response to therapies of many cancers. Therefore, identified functional SNPs in this pathway could affect many types of cancers, and help us to understand and intervene in all stages of the disease.

We have demonstrated that SNPs in the p53 tumour suppressor pathway, which associate with robust molecular and cancer phenotypes, can be utilized to address fundamental questions about human cancer, and potentially offer clinical utility. When we began, decades of research had clearly shown that genetic manipulation of p53 signalling can dramatically affect susceptibility to a broad range of cancers in mice and humans. However, most evidence has been restricted to rare inherited mutations found in families with Li-Fraumeni Syndrome (LFS) and common somatic mutations found in cancer genomes. We have systematically explored the possibility that commonly inherited genetic variants in the p53 pathway also have a significant role in susceptibility and progression in a broad range of cancers. We have developed and implemented screens to identify functional p53 tumour suppressor pathway SNPs and identified common variants that affect: the biological process of transcriptional regulation, gene expression and cellular chemosensitivity; and the risk and/or progression of epithelial, mesenchymal and blood cancers. Our data not only provided further evidence that functional p53 SNPs could serve as biomarkers for cancer risk, but also demonstrate that p53 pathway SNPs can provide insights into p53 biology, such as its role in tumour suppression, evolution and chemo-sensitivities.


 

Research

  • Genetics and Genomics
  • Bioinformatics
  • Computational biology
  • Drug discovery
  • SNP typing
  • Whole genome sequencing
  • Data mining
  • Molecular and Cellular Biology

Other activities

  • 2015-2019         Associate Professor of the University of Oxford
  • 2014-2019         Associate Member of Ludwig Institute of Cancer Research
  • 2008-2014         Assistant Member of Ludwig Institute of Cancer Research
  • 2014-2015         University Research Lecturer of the University of Oxford
  • 2008-2011         Nuffield Department of Medicine Leadership Fellow of the University of Oxford

Publications

Zhang, P., Christen, S.P., and Bond, G.L. (2019). JMCB Symposium 2019: The Legend of p53 vs. Cancer. J Mol Cell Biol 11, 628-629.

Chen, S., Wu, J., Zhong, S., Li, Y., Zhang, P., Ma, J., Ren, J., Tan, Y., Wang, Y., Au, K.F., Siebold, C., Bond, G.L., Chen, Z., Lu, M., Jones, Y., and Lu, X. (2019). iASPP mediates p53 selectivity through a modular mechanism fine-tuning DNA recognition. Proc Natl Acad Sci U S A 116, 17470-17479.

Moore, S., Jarvelin, A.I., Davis, I., Bond, G.L., and Castello, A. (2018). Expanding horizons: new roles for non-canonical RNA-binding proteins in cancer. Curr Opin Genet Dev 48, 112-120.

Leroy, B., Ballinger, M.L., Baran-Marszak, F., Bond, G.L., Braithwaite, A., Concin, N., Donehower, L.A., El-Deiry, W.S., Fenaux, P., Gaidano, G., et al. (2017). Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice. Cancer Res 77, 1250-1260.

Stracquadanio, G., Wang, X., Grawenda, A.M., Wallace, M., Zhang, P., Hewitt, J., Zeron-Medina, J., Catro-Giner, F., Tomlinson, I.P., Goding, C.R., Shuster-Boeckler, B., Bell, D.A., and Bond, G.L. (2016)The importance of p53 pathway genetics in inherited and somatic cancer genomes. Nature Reviews Cancer Original Analysis

Grawenda, A.M., Moller, E.K., Lam, S., Repapi, E., Teunisse, A.F., Alnaes, G.I., Borresen-Dale, A.L., Kristensen, V.N., Goding, C.R., Jochemsen, A.G., Edvardsen, H. and Bond, G.L. (2015). Interaction between p53 Mutation and a Somatic HDMX Biomarker Better Defines Metastatic Potential in Breast Cancer. Cancer Res.

Lewis, A., Freeman-Mills, L., de la Calle-Mustienes, E., Giraldez-Perez, R.M., Davis, H., Jaeger, E., Becker, M., Hubner, N.C., Nguyen, L.N., Zeron-Medina, J.,Bond, G., Stunnenberg, H. G., Carvajal, J. J., Gomez-Skarmeta, J. L., Leedham, S., and Tomlinson, I. (2014). A polymorphic enhancer near GREM1 influences bowel cancer risk through differential CDX2 and TCF7L2 binding. Cell Rep 8, 983-990.

Zeron-Medina, J., Wang, X., Repapi, E., Campbell, M.R., Su, D., Castro-Giner, F., Davies, B., Peterse, E.E.P., Sacilotto, N., Walker, G.J., Terzian, T., Tomlinson, I.P., Box, N.F., Meinshausen, N., De Val, S., Bell, D.A., and Bond, G.L. (2013) A Polymorphic p53 Response Elment in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection. Cell 155, 410-422.

Thomas, D.M., Savage, S.A., and Bond, G.L. (2012). Hereditary and environmental epidemiology of sarcomas. Clin Sarcoma Res 2, 13.

Grochola, L.F., Zeron-Medina, J., Repapi, E., Finlayson, A., Cai, Y., Atwal, G.S., and Bond, G.L. (2012) The Inheritance of p53. In p53 in the Clinics. Springer Science and Business Media, New York, p. 25-46

Lenos, K., Grawenda, A., Grochola, L.F., Taubert, H., Wurl, P., Bartel, F., Lodder, K., Kuijjer, M.L., Teunisse, A., Hogendoorn, P.C.W., Cleton-Jansen, A.M., Bond, G.L.*, and Jochemsen, A.G.* (2012) Alternative Splicing of the p53 Inhibitor HDMX offers a Superior Prognostic Biomarker than p53 Mutation in Human Cancer. Cancer Res*co-corresponding authors

Yee, K.S., Grochola, L., Hamilton, G., Grawenda, A., Bond, E.E., Taubert, H., Wurl, P., Bond, G.L., and O'Neill, E. (2012). A RASSF1A Polymorphism Restricts p53/p73 Activation and Associates with Poor Survival and Accelerated Age of Onset of Soft Tissue Sarcoma. Cancer Res 72, 2206-2217. 

Greither, T., Wurl, P., Grochola, L., Bond, G., Bache, M., Kappler, M., Lautenschlager, C., Holzhausen, H.J., Wach, S., Eckert, A.W., and Taubert, H. (2012). Expression of microRNA 210 associates with poor survival and age of tumor onset of soft-tissue sarcoma patients. Int J Cancer 130, 1230-1235.

Post, S.P., Quintas-Cardama, A., Pant, V., Iwakuma, T., Hamir, A., Jackson, J.G., Maccio, D.R., Bond, G.L., Johnson, D.G., Levine, A.J., Lozano, G. (2010) A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18, 220-230

Vazquez, A., Grochola, L.F., Bond, E.E., Levine, A.J., Taubert, H., Muller, T.H., Wurl, P., and Bond, G.L. (2010). Chemosensitivity Profiles Identify Polymorphisms in the p53 Network Genes 14-3-3 and CD44 That Affect Sarcoma Incidence and Survival. Cancer Research 70, 172-80.

Grochola, L.F., Zeron-Medina, J., Meriaux, S., and Bond, G.L. (2010). Single-nucleotide polymorphisms in the p53 signaling pathway. Cold Spring Harb Perspect Biol 2, a001032.

Grochola, L. F., Vazquez, A., Bond, E. E., Wurl, P., Taubert, H., Muller, T. H., Levine, A. J., and Bond, G. L. (2009). Recent natural selection identifies a genetic variant in a regulatory subunit of protein phosphatase 2A that associates with altered cancer risk and survival. Clin Cancer Res 15, 6301-6308.

Atwal, G. S., Kirchhoff, T., Bond, E. E., Montagna, M., Menin, C., Bertorelle, R., Scaini, M. C., Bartel, F., Bohnke, A., Pempe, C., Gradhand, E., Hauptmann, S., Offit, K., Levine, A. J., and Bond, G. L. (2009). Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene. Proc Natl Acad Sci USA 106, 10236-10241.

Vazquez, A., Bond, E. E., Levine, A. J., and Bond, G. L. (2008). The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 7, 979-987.

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