Background: Loss of TP53 function through gene mutation is a critical event in the development and progressionof many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneityamongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whetherTP53 mutations classified as functionally inactive (£20% of wildtype transactivation ability) had different prognosticand predictive values in CRC compared with mutations that retained significant activity.Materials and methods: TP53 mutations within a large, international database of CRC (n = 3583) were classifiedaccording to functional status for transactivation.Results: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) thanproximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen inadvanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) andlymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only inpatients with Dukes’ stage D tumours (RR = 1.71, 95%CI 1.25–2.33, P < 0.001). Patients with Dukes’ C stagetumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functionalstatus for transactivation ability.Conclusions: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC andare associated with worse prognosis in this stage of disease.
|Number of pages||6|
|Journal||Annals of Oncology|
|Publication status||Published - 2006|
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