Translational studies in colorectal and ovarian cancer
Division of Cancer Research
Jacqui Wood Cancer Centre
University of Dundee
James Arrott Drive
Ninewells Hospital And Medical School
+(44) 01382 383252
Gillian Smith graduated from the University of Edinburgh in 1988 with a BSc (Hons) degree in Chemistry and in 1992 with a PhD in Medicine. Her PhD work was funded by the Imperial Cancer Research Fund (now CRUK) and focussed on novel mechanisms of cytochrome P450 regulation in human tumours. Following a brief period in the University of Edinburgh Department of Pathology, Gillian moved to Dundee in 1993 to join the newly formed Biomedical Research Centre at the University of Dundee, based in Ninewells Hospital & Medical School. She spent several months in the Department of Clinical Pharmacology, Uppsala University in Sweden in 1997 before returning to Dundee as a Post-Doctoral Research Fellow, Senior Scientist, then Senior Lecturer in the Division of Cancer Research, Medical Research Institute, where she runs a translational research group focussing on inter-individual differences in disease progression and treatment response in cancer patients.
We are interested in understanding the molecular events which make individual cancer patients different – both in terms of disease progression and in treatment response. We have developed successful translational research programmes in colorectal and ovarian cancer, working closely with clinical colleagues. Our colorectal research programme (in collaboration with Professor Bob Steele, Professor Frank Carey, Professor Alastair Munro and Dr Norman Pratt) has focussed on individuality in mutation burden in colorectal tumours and the role of the K-Ras oncogene in tumour progression – we are currently extending this work to identify molecular signatures associated with the adenoma/carcinoma transition and with the development of metastatic disease. Additional work is focused on the identification of novel drug resistance mechanisms following 5-FU and oxaliplatin-based chemotherapy regimens. In complementary experiments in ovarian cancer, we are working with Dr Michelle Ferguson and Professor Simon Herrington to understand histotype-specific differences in gene expression in ovarian tumours which influence disease progression and treatment response. Our work in ovarian cancer is currently focussed on a variety of growth factor signalling pathways, differential expression of which we have shown to influence both tumour progression and response to platinum-based chemotherapy. We have recently commissioned novel clinical studies to extend our analysis of key signalling pathways and to identify novel mechanisms of drug resistance, a common treatment-limiting complication in the clinical management of ovarian cancer.
- Deeni, Y.Y., Ibbotson, S.H., Woods, J.A, Wolf, C.R. and Smith, G. Cytochrome P450 CYP1B1 interacts with 8-methoxypsoralen (8-MOP) and influences psoralen-ultraviolet A (PUVA) sensitivity. PLOS ONE, 8, e75494 (2013).
- Smith, G., Ng, M.T.H., Shepherd, L., Herrington, C.S., Gourley, C., Ferguson, M.J., and Wolf, C.R. Individuality in fibroblast growth factor-1 (FGF1) expression significantly influences survival and platinum resistance in ovarian cancer patients. British Journal of Cancer, 107, 1327-1336 (2012).
- McNeilly, A.D., Harty, H.F., Woods, J.A., Ibbotson, S.H., Wolf, C.R. and Smith, G. Characterisation of a human keratinocytes HaCaT cell line model to study the regulation of cytochrome P450 CYP2S1. Drug Metabolism and Disposition, 40, 283-289 (2012).
- Ibbotson, S.H., Dawe, R.S., Weidlich, S., Dinkova Kostova, A., Farr, P.M., Ferguson, J., Wolf, C.R. and Smith, G. Glutathione S-transferase M1 (GSTM1) genotype is associated with serum 8-methoxy psoralen concentration and PUVA erythemal sensitivity. British Journal of Dermatology, 166, 380-388 (2012).
- Weidlich, S., Walsh, K., Crowther, D., Burczynski, M.E., Feuerstein, G., Carey, F.A., Steele, R.J., Wolf, C.R., Miele, G. and Smith, G. (2011) Pyrosequencing-based methods reveal marked inter-individual differences in oncogene mutation burden in human colorectal tumours. Br J Cancer, 105, 246-254 (2011).
- Smith, G., Weidlich, S., Dawe, R.S. and Ibbotson, S.H. Glutathione S-transferase M1 (GSTM1) genotype but not GSTT1 or MC1R genotype influences erythemal sensitivity to narrow band (TL-01) UVB phototherapy. Pharmacogenetics and Genomics, 21, 217-224 (2011).
- Northwood, E.L., Elliott, F., Forman, D., Barrett, J.H., Wilkie, M.J.V, Wolf, C.R., Bishop, D.T. and Smith, G. Metabolic Gene Polymorphisms, Diet and Risk of Colorectal Adenoma. Pharmacogenetics and Genomics, 20, 315-326 (2010).
- Smith, G., Bounds, R., Wolf, H., Steele, R.J.C., Carey, F. and Wolf, C.R. Activating K-Ras mutations outwith “hotspot” codons in sporadic colorectal tumours – implications for personalised cancer medicine. Br J Cancer, 102, 693-703 (2010).
- Wilkie, M.J.V., Smith, G., Day, R.K., Matthews, K., Smith, D., Blackwood, D., Reid, I.C. and Wolf, C.R. Polymorphisms in the SLC6A4 and HTR2A genes influence treatment outcome following antidepressant therapy. Pharmacogenomics J, 9, 61-70 (2009).
- Lightfoot, T.J., Barrett, J.H., Bishop, D.T., Northwood, E.L., Smith, G., Wilkie, M.J.V., Steele, R.J.C., Carey, F.A., Key, T.J., Wolf, C.R. and Forman, D. Methylene tetrahydrofolate reductase (MTHFR) genotype modifies the chemopreventive effect of folate in colorectal adenoma, but not colorectal cancer. Cancer Epidemiol Biomarkers Prev, 17, 2421-2430 (2008).
- Smith, G., Wilkie, M.J.V., Deeni, Y.Y., Farr, P.M., Ferguson, J., Wolf, C.R. and Ibbotson, S.H. Melanocortin 1 receptor (MC1R) genotype influences erythemal sensitivity to PUVA. Br J Dermatol, 157, 1230-1234 (2007).
- Wilkie, M.J.V., Smith, D., Reid, I.C., Day, R.K., Matthews, K. and Wolf, C.R., Blackwood, D., Smith, G. A splice site polymorphism in the G-protein b subunit influences antidepressant efficacy in unipolar and early onset depression. Pharmacogenetics and Genomics, 17, 207-215 (2007).
- Leslie, A., Stewart, A., Baty, U., Mecham, D., McGreavey, L., Smith, G., Wolf, C.R., Sales, M., Pratt, N.R., Steele, R.J.C. and Carey, F.A. Chromosomal changes in colorectal adenomas: relationship to gene mutations and potential for clinical utility. Genes, Chromosomes and Cancer, 45, 126-135 (2006).
- McGreavey, L.E., Turner, F., Smith, G., Boylan, K., Bishop, D.T., Forman, D., Wolf, C.R. and Barrett, J.A. No evidence that polymorphisms in CYP2C8, CYP2C9, UGT1A6, PPARd and PPARg Act as Modifiers of the Protective Effect of Regular NSAID use on the Risk of Colorectal Carcinoma. Pharmacogenetics and Genomics, 15, 713-721 (2005).
- Conlin, A., Smith, G., Carey, F.A., Wolf, C.R. and Steele, R.J.C. The Prognostic Significance of K-Ras, p53 and APC Mutations in Colorectal Carcinoma. Gut, 54, 1283-1286 (2005).
- Turner, F., Smith, G., Sachse, C., Lightfoot, T., Garner, R.C., Wolf, C.R., Forman, D., Bishop, D.T. and Barrett, J.H. Vegetable, fruit and meat consumption and potential risk modifying genes in relation to colorectal cancer. Int. J. Cancer, 112, 259-264 (2004)
- Barrett, J.H., Smith, G., Waxman, R., Gooderham, N., Lightfoot, T., Garner, R.C., Augustsson, K., Wolf, C.R., Bishop, D.T, Forman. D. and the Colorectal Cancer Study Group. Investigation of interaction between N-acetyltransferase 2 and heterocyclic amines as potential risk factors for colorectal cancer. Carcinogenesis 24, 275-282 (2003).
- Smith, G., Wolf, C.R., Deeni, Y.Y., Dawe, R.S., Evans, A.T., Comrie, M.M., Ferguson, J. and Ibbotson, S.H. Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases. Lancet 261, 1336-1343 (2003).
- Leslie, A., Pratt, N.R., Gillespie, K., Sales, M., Kernohan, N.M., Smith, G., Wolf, C.R., Carey, F.A. and Steele, R.J. Mutations of APC, K-ras, and p53 are associated with specific chromosomal aberrations in colorectal adenocarcinomas. Cancer Res. 63, 4656-4661 (2003).
- Smith, G., Carey, F.A., Beattie, J., Wilkie, M.J., Lightfoot, T.J., Coxhead, J., Garner, R.C., Steele, R.J. and Wolf, C.R. Mutations in APC, Kirsten-Ras, and p53--alternative genetic pathways to colorectal cancer. Proc. Natl. Acad. Sci. (USA) 99, 9433-9438 (2002).
- Sachse, C., Smith, G., Wilkie, M.J., Barrett, J.H., Waxman, R., Sullivan, F., Forman, D., Bishop, D.T., Wolf, C.R. and the Colorectal Cancer Study Group. A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer. Carcinogenesis 23, 1839-1849 (2002).
- Smith, G., Dawe, R.S., Evans, A.T., Comrie, M.M., Ferguson, J., Wolf, C.R. and Ibbotson, S.H. Expression and regulation of cytoprotective genes by ultraviolet radiation in skin of patients with psoriasis. J. Invest. Dermatol. 119, 740 (2002).
MRes Cancer Biology, Module Leader, Lecturer and Project Supervisor
BSc Biological/Biomedical Sciences Level 4 Cancer Biology Module Leader
MBChB Year 1 SSC Essay supervisor
MBChB Year 3 SSC in Laboratory Research supervisor
BMSc Project Supervisor
Edward Amankwatia (current PhD student): microRNA expression in colorectal tumours: identification of novel mechanisms of gene regulation
Emma Joseph (current PhD student): Specificity of fibroblast growth factor signalling in human tumours – identification of novel therapeutic targets?
Aparajitha Vaidyanathan, MRes Cancer Biology 2013 with Distinction. Characterisation of novel drug resistance mechanisms in ovarian cancer.
Bianca Ihrig, MRes Cancer Biology 2012 with Distinction. Characterisation of novel drug resistance mechanisms in ovarian cancer.
Lynne Shepherd, MSc by Research 2011. Characterisation of inter-individual differences in gene expression associated with clinical outcome in ovarian cancer.
Rebecca Bounds, PhD, 2009: Characterisation of novel mutations in the K-Ras oncogene.
Murray Wilkie, MSc by Research 2005. A pharmacogenetic basis for inter-individual variation in response to antidepressant therapy.