Colorectal cancer kills approximately 500 000 people worldwide each year , thus treatments which produce only modest improvements in survival may have an enormous health impact. Current practice is to base therapeutic decisions and prognostic advice on clinico-pathological data, however within conventional staging groups many genetic and molecular tumour subtypes exist. This heterogenicity of tumour genotypes accounts for much of the observed variation in recurrence rates and clinical responses to available therapies.
Advances in our understanding of the molecular biology of colorectal cancer have fuelled the search for novel molecular prognostic markers with which to complement existing staging systems. Applied to clinical practice, these putative markers could be used to identify groups of patients with differing relative risks of recurrence and improve patient stratification for adjuvant treatment.
Immunohistochemical studies in colorectal cancer have tended to investigate expression of individual proteins in relation to prognosis, and relatively few studies have focused on the analysis of multiple markers in combination. However, one such combination which may be of value in colorectal cancer is the combined p53 / Bcl-2 phenotype, as suggested by Manne et al, who described the p53/Bcl-2 phenotype of 134 patients with Dukes stage A-D tumours, finding that this combination gave independent prognostic information which was superior to that of either marker on its own . The same group have subsequently shown in a larger cohort of 234 patients with tumours of the distal colo-rectum that combined p53/Bcl-2 analysis may provide stronger prognostic information than nodal status . Other researchers have reported similar findings in differing groups of colorectal cancer patients [4, 5], with the p53(-)/Bcl-2(+) subset appearing to define a group of patients who appear to have a prolonged survival, although this has not always retained independence on multivariate analysis [6, 7]. Alternatively, it has been suggested that opposing p53(+)/Bcl-2(-) phenotype defines a particularly poor prognosis subset , or that Bcl-2 positivity in combination with either p53, p21 or mdm-2 confers a good prognosis .
Since its first description in 1998, tissue microarray (TMA) analysis  has been employed for the immunohistochemical analysis of target protein expression in a wide range of primary tumour types. Initial fears that the reduced amount of individual tumour tissue analysed using this technique might not be representative of the tumour as a whole appear largely unfounded , and the strengths of this approach lie in its ability to provide a rapid turnover of results from very large patient cohorts, whilst reducing variability in experimental conditions and reducing costs . Two previous studies have utilised tissue microarray technology to investigate the combination of p53/Bcl-2 in rectal cancer. In the first, Hoos et al, studied 100 patients with lymph-node negative rectal cancer, and found an increased number of deaths in the patients with p53(+)/Bcl-2(-) tumors (7/33, 21.2%) compared with the p53(-)/Bcl-2(+) group (2/13, 15.4%) , and a recent study of 269 patients with Dukes stage A-D rectal cancer reported a lower rate of metastatic disease in p53(-)/Bcl-2(+) tumours, with p53(+)/Bcl-2(-) tumours showing a worse outcome .
The aim of the present study was to investigate the prognostic significance of the combined p53/Bcl-2 phenotype in a large scale, representative sample of colorectal cancers using tissue microarrays, in order to determine the potential utility of this combination of molecular markers in guiding treatment of patients in the UK.