Academic Staff

Dr Keith W. Brown

Ph.D. (1983) University of Birmingham

Reader in Molecular Pathology

Contact Details
Dept. of Cellular & Molecular Medicine, University of Bristol,
School of Medical Sciences, Bristol, BS8 1TD
Tel: +44 (0)117 33 12071 (internal 12071)
Fax: +44 (0)117 33 12091
Email: keith.brown@bristol.ac.uk

Past Research

Human cancer susceptibility syndromes
Immunoassay of human brain proteins
In vitro properties of human epithelial cancer cells
Extracellular matrix changes in malignant transformation

Current Research

My research interests are in the molecular genetics of children's cancers, concentrating in particular on two common cancers; Wilms' tumour of the kidney and neuroblastoma, a cancer of the sympathetic nervous system.

Epigenetics of childhood cancers:

Epigenetic alterations are heritable modifications of DNA that do not affect the primary sequence, such as methylation of cytosines in CpG dinucleotides. DNA methylation at CpG residues affects gene expression by directly inhibiting transcription factor access to DNA or indirectly by attracting methyl-binding proteins that associate with modifiers of chromatin structure, such as histone deacetylases. Cancers usually have an overall hypomethylation of the genome, probably leading to chromosomal instability, accompanied by gene-specific hypermethylation that inactivates tumour suppressor genes.

The aim of this project is to characterize genome-wide DNA methylation changes in clinically important childhood cancers such as Wilms’ tumour and neuroblastoma. This is being achieved by the use of human promoter microarrays, hybridized with tumour DNA enriched for methylated sequences. This technique gives genome-wide coverage of methylation changes in cancer, thus identifying new prognostic markers and targets for therapy. This will identify genes that are abnormally methylated in childhood cancers, which will then be further studied using functional analyses in cultured cells.

The results of this work are designed to give the following outcomes that could impact on the clinical management of childhood cancers:

Identification of new prognostic markers.
Identification of genes that represent new targets for therapy.
Determine whether the pattern of overall genome methylation in would allow therapy based on targeting the mechanisms that regulate DNA methylation.

Novel loci involved in the development of Wilms' tumour
Positional cloning techniques have been used to map and identify the genes present at a novel chromosomal translocation at 7p involved in Wilms' tumour. This area is also deleted in a subset of mainly aggressive Wilms' tumours. Candidate gene approaches and the results of epigenetic (see above) and other genomic approaches are being used to identify genes that my be genetically or epigenetically deregulated in this region of chromosome 7 in Wilms' tumour. This will then lead on to functional studies of these genes, as we have already developed for the WT1 gene.

Our work is supported by CLIC Sargent
Our laboratory is known as the CLIC Sargent research unit, after our major sponsors. Click here for a brief summary of the history and work of the unit.

Present co-workers

Karim Malik
Anthony Dallosso
Anne Hancock
Sally Malik
Marianna Szemes
Yifan Li
Jessica Charlet

Recent Publications

Vuononvirta, R., Sebire, N.J., Dallosso, A.R., Reis-Filho, J.S., Williams, R.D., Mackay, A., Fenwick, K., Grigoriadis, A., Ashworth, A., Pritchard-Jones, K., Brown, K.W., Vujanic, G.M. and Jones, C. (2008) Mapping the molecular alterations in IGF2-associated Wilms tumorigenesis – perilobar nephrogenic rests as non-obligate molecular genetic precursor lesions. Clin. Cancer Res. in press.

Brown, K.W., Power, F., Moore, B., Charles, A.K. and Malik, K.T.A. (2008) Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development. Mol. Cancer Res. 6, 1114-1123.

Dallosso, A.R., Hancock, A.L., Malik, S., Salpekar, A., King-Underwood, L., Pritchard-Jones, K., Peters, J., Moorwood, K., Ward, A., Malik, K.T.A. and Brown, K.W. (2007) Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer. RNA 13, 2287-2299.

Chilukamarri, L., Hancock, A.L., Malik, S., Zabkiewicz, J., Baker, J.A., Dallosso, A.R., Huang, T.H.M., Royor-Pokora, B., Brown, K.W. and Malik, K. (2007) Hypomethylation and aberrant expression of the glioma pathogenesis-related 1 gene in Wilms' tumours. Neoplasia 9, 970-978.

Hancock, A.L., Brown, K.W., Moorwood, K., Moon, H., Holmgren, C., Mardikar, S.H., Dallosso, A.R., Klenova, E., Loukinov, D., Ohlsson, R., Lobanenkov, V.V. and Malik, K. (2007) A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS, and exhibits sequential epigenetic defects during Wilms' tumourigenesis. Human Molec. Gen. 16, 343-354.

Dallosso, A.R., Hancock, A., Brown, K.W., Williams, A.C., Jackson, S. and Malik, K.T.A. (2004) Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours. Human Molec. Gen. 13(4), 405-415.

Vernon, E.G., Malik, K.T.A., Reynolds, P.A., Powlesland, R.M., Dallosso, A.R., Brown, K.W., Henthorn, K., Green, E.D. and Jackson, S. (2003) The parathyroid hormone-responsive B1 gene is interrupted by a t(1;7)(q42;p15) breakpoint associated with Wilms' tumour. Oncogene 22, 1371-1380.

Greenhalgh, K.L., Howell, R.T., Bottani, A., Ancliff, P.J., Brunner, H.G., Verschuuren-Bemelmans, C.C., Vernon, E.G., Brown, K.W. and Newbury-Ecob, R.A. (2002) Thrombocytopenia-absent radius syndrome: a clinical genetic study. J. Med. Genet. 39, 876-881.

Cummings, M. and Brown, K.W. (2001) Low frequency of genetic lesions in Wilms tumors by representational difference analysis. Cancer Genet. Cytogenet. 127(2), 155-160.

Brown, K.W., Jackson, S., Moorwood, K., Hancock, A., Dallosso, A.R. and Malik, K.T.A. (2001) Epigenetics of Wilms' tumour. Brit. J. Cancer 85(supp.1), 30.

Malik, K.T.A. and Brown, K.W. (2001) Epigenetic gene deregulation in cancer. Brit. J. Cancer 83(12), 1583-1588.

Malik, K.T.A., Yan, P., Huang, TH-M. and Brown, K.W. (2001) Wilms' tumor: A paradigm for the new genetics. Oncology Res. 12, 441-449.

Brown, K.W. and Malik, K.T.A. (2001) The molecular biology of Wilms' tumour. Exp. Revs. Molec. Med. 14 May, http://www-ermm.cbcu.cam.ac.uk/01003027h.htm

Malik, K. and Brown, K.W. (2000) Epigenetic gene deregulation in cancer. Brit. J. Cancer 83, 1538-1588.

Malik, K., Salpekar, A., Hancock, A., Moorwood, K., Jackson, S., Charles, A. and Brown, K.W. (2000) Identification of differential methylation of the WT1 antisense regulatory region and relaxation of imprinting in Wilms' tumor. Cancer Research 60, 2356-2360.

Powlesland, R.M, Charles, A.K., Malik, K.T.A, Reynolds, P.A., and Brown, K.W. (2000) Loss of heterozygosity at 7p in Wilms' tumour development. Brit. J. Cancer 82, 323-329.