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  • Clinical Implications
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Clinical significance of prognostic and predictive markers in colorectal cancer

The Pharmacogenomics Journal volume 2, pages 209–216 (2002)Cite this article

Colorectal cancer (CRC) is the second most common cause of cancer death in the US. Approximately 130 000 new cases of CRC are diagnosed in the US each year with an annual mortality of approximately 56 000 people. In the post-operative setting, there is clear evidence that offering adjuvant therapy significantly improves survival in stage III CRC, however, the management of stage II disease is an area of controversy and debate. The 5-year survival for stage II patients is approximately 75%, indicating that the majority are cured by surgery alone, and many patients who would have been cured by surgery undergo chemotherapy unnecessarily. Furthermore, some patients who are not recommended to receive adjuvant treatment may benefit from chemotherapy. Recent studies have started to define prognostic molecular markers that identify those patients at risk of relapse after surgery and who may benefit most from chemotherapy (Table 1). Furthermore, molecular markers are being identified that predict whether a tumour will respond to a particular chemotherapy. In addition, some markers may have therapeutic value by predicting the degree of systemic toxicity for a particular treatment. For such studies tumour DNA can be analysed to identify genetic changes such as point mutations, loss of heterozygosity (LOH), gene amplification and microsatellite instability (MSI). In addition, the expression of individual genes can be assessed at the levels of mRNA and protein using the techniques of real-time reverse transcription PCR and immunohistochemistry (IHC) respectively. The ultimate goal of this research is the tailoring of treatment to the molecular phenotypes of tumour and patient. This review highlights potentially important prognostic and predictive markers in CRC. Due to space restrictions many worthy contributions could not be cited.

Table 1 Prognostic molecular markers in colorectal cancer
Full size table

More than 75% of CRCs have lost a portion of chromosome 17p or 18q, or both. The 17p segment contains p53, which is regarded as one of the most important tumour suppressor genes. It has a number of key functions such as DNA damage repair, initiation of cell cycle checkpoints and initiation of apoptosis.3 p53 has been the most extensively studied molecular marker in patients with CRC and mutations have been found in 40–60% of cases.2 Missense mutations of the p53 gene result in production of a protein with a longer half-life, therefore, detection of increased p53 expression by IHC has been used as a surrogate for p53 mutation in many studies. However, this assumption has been shown to be valid in only 60–80% of cases in studies that have compared p53 expression measured by IHC with p53 mutations analysed by DNA sequencing.4 Despite numerous investigations into the prognostic value of p53 overexpression in patients with CRC, the issue still remains controversial. Many studies have been statistically underpowered, and the issue is further complicated by the use of different antibodies which have varying levels of sensitivity and capacity for detecting mutant forms of p53. Studies of at least 100 patients with CRC using p53 monoclonal antibodies have generally found that p53 overexpression was associated with worse prognosis.5,6 This association has not been a consistent observation as some studies have found the opposite,7 or no correlation.8,9 However, the majority of DNA sequencing studies have shown a significantly shorter survival time in patients with mutant p53.10 Data from studies in cell line models have suggested that p53 status influences 5FU chemosensitivity.11,12 This has been borne out in several clinical studies, for example Ahnen et al found that patients with stage III CRC whose tumours overexpressed p53 did not derive significant survival benefit from adjuvant 5FU-based treatment, whereas those without p53 overexpression did.13 However, other studies have found no correlation between p53 status and response to 5FU-based chemotherapy.14

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  1. Department of Oncology, Cancer Research Centre, Queen's University Belfast, Belfast, Northern Ireland

    D B Longley, U McDermott & P G Johnston

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Longley, D., McDermott, U. & Johnston, P. Clinical significance of prognostic and predictive markers in colorectal cancer. Pharmacogenomics J 2, 209–216 (2002). https://doi.org/10.1038/sj.tpj.6500124

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