Research at LICR Oxford Dr Gareth Bond

Research Areas

The Identification and Analysis of Genetic Variants in Cancer Signalling Pathways that Affect Human Cancer Risk and Progression

The Identification and Analysis of Genetic Variants that Mediate the Responses to Cancer Therapies

Dr Gareth Bond

Contact Dr Gareth Bond

Research Overview

The long-term goals of our research programme are to understand the contribution of heritable genetics to human cancer and to utilise this knowledge in the personalisation of prevention and treatment strategies. The task of identifying variations in the human genetic code that affect cancer risk, progression and survival is complicated by the extremely large size of the human genome and the relative abundance of variations found between individuals. To overcome this, our approach is to focus on biologically relevant signalling pathways that are likely to be involved in cancer causation and progression. For example, a large body of evidence strongly suggests that the genes that make up the p53 tumour suppressor pathway are central both in reducing cancer frequency in vertebrates and in mediating the response of commonly used cancer therapies. The p53 pathway is a cellular stress response pathway that is activated upon stresses such as DNA damage and oncogene activation. Once activated, this signalling pathway initiates cellular responses such as DNA repair, cell cycle arrest or cell death. One of the main functions of this signal transduction pathway is to ensure the fidelity of the genome, the result of which is the suppression of tumour formation.

We, and others, have shown allelic differences for a SNP in the p53 tumour suppressor pathway (MDM2 SNP309) in cancer risk and outcome in both humans and mouse models, thereby demonstrating that the inherited genetics of the p53 network could be utilised to further define patients in their abilities to suppress tumour formation and respond to therapies. Surprisingly, however, few such variants have been identified in this or other signalling pathways that are altered in cancer. Our research programme integrates computational, molecular, cellular and human genetic approaches, to identify clinically relevant SNPs that affect cancer risk, progression, metastasis and response to therapy in this and other important cancer signalling pathways. Once identified, we characterise their impact on key regulatory mechanisms and their biological roles in cell fate decisions with a focus on their interactions with other SNPs, known risk factors and therapeutics.

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Key Publications

Post SP, Quintas-Cardama A, Pant V, Iwakuma T, Hamir A, Jackson JG, Maccio DR, Bond GL, Johnson DG, Levine AJ, Lozano G. (2010) A high-frequency regulatory polymorphism in the p53 accelerates tumor development. Cancer Cell 18: 220-30. View as a PDF

Vazquez, A., Grochola, L.F., Bond, E.E., Levine, A.J., Taubert, H., Muller, T.H., Wurl, P., and Bond, G.L. 2009. Chemosensitivity Profiles Identify Polymorphisms in the p53 Network Genes 14-3-3{tau} and CD44 That Affect Sarcoma Incidence and Survival. Cancer Res. View on PubMed | View as a PDF

Grochola, L.F., Zeron-Medina, Meriaux, and Bond, G.L. 2009 Single-nucleotide Polymorphisms in the p53 Signaling Pathway. Cold Spring Harb Perspect Biol. View as a PDF

Grochola LF, Vazquez A, Bond EE, Wurl P, Taubert H, Muller TH, Levine AJ, Bond GL. 2009. Recent Natural Selection Identifies a Genetic Variant in a Regulatory Subunit of Protein Phosphatase 2A that Associates with Altered Cancer Risk and Survival. Clinical Cancer Research. View on PubMed | View as a PDF

Atwal GS, Kirchhoff T, Bond EE, Monagna M, Menin C, Bertorelle R, Scaini MC, Bartel F, Bohnke A, Pempe C, Gradhand E, Hauptmann S, Offit K, Levine AJ, Bond GL. 2009. Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene. Proceedings of the National Academy of Sciences of the United States of America. View on PubMed | View as a PDF

Vazquez A, Bond EE, Levine AJ, Bond GL. 2008. The genetics of the p53 pathway, apoptosis and cancer therapy. Nature reviews. Drug discovery, 7 (12), pp. 979-87. View on PubMed | View as a PDF

Atwal GS, Rabadan R, Lozano G, Strong LC, Ruijs MW, Schmidt MK, van't Veer LJ, Nevanlinna H, Tommiska J, Aittomaki K, Bougeard G, Frebourg T, Levine AJ, Bond GL. 2008. An information-theoretic analysis of genetics, gender and age in cancer patients. PLoS ONE, 3 (4), pp. e1951. View on PubMed | View as a PDF

Bond GL, Levine AJ. 2007. A single nucleotide polymorphism in the p53 pathway interacts with gender, environmental stresses and tumor genetics to influence cancer in humans. Oncogene, 26(9), pp. 1317-23. View on PubMed | View as a PDF

Bond GL, Menin C, Bertorelle R, Alhopuro P, Aaltonen LA, Levine AJ. 2006. MDM2 SNP309 accelerates colorectal tumour formation in women. Journal of medical genetics, 43 (12), pp. 950-2. View on PubMed | View as a PDF

Atwal GS, Bond GL, Metsuyanim S, Papa M, Friedman E, Distelman-Menachem T, Ben Asher E, Lancet D, Ross DA, Sninsky J, White TJ, Levine AJ, Yarden R. 2007. Haplotype structure and selection of the MDM2 oncogene in humans. Proceedings of the National Academy of Sciences of the United States of America, 104 (11), pp. 4524-9. View on PubMed | View as a PDF

Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ. 2006. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer research, 66 (10), pp. 5104-10. View on PubMed | View as a PDF

Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ. 2004. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell, 119 (5), pp. 591-602. View on PubMed | View as a PDF

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