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Annals of Oncology Advance Access published online on March 8, 2006
Annals of Oncology, doi:10.1093/annonc/mdl035
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© 2006 European Society for Medical Oncology
Received November 24, 2005
Revised January 26, 2006
Accepted January 31, 2006

original article

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

B. Iacopetta 1 *, A. Russo 1, V. Bazan 1, G. Dardanoni 1, N. Gebbia 1, T. Soussi 1, D. Kerr 1, H. Elsaleh 1, R. Soong 1, D. Kandioler 1, E. Janschek 1, S. Kappel 1, M. Lung 1, C.-S. S. Leung 1, J. M. Ko 1, S. Yuen 1, J. Ho 1, S. Y. Leung 1, E. Crapez 1, J. Duffour 1, M. Ychou 1, D. T. Leahy 1, D. P. O'Donoghue 1, V. Agnese 1, S. Cascio 1, G. Di Fede 1, L. Chieco-Bianchi 1, R. Bertorelle 1, C. Belluco 1, W. Giaretti 1, P. Castagnola 1, E. Ricevuto 1, C. Ficorella 1, S. Bosari 1, C. D. Arizzi 1, M. Miyaki 1, M. Onda 1, E. Kampman 1, B. Diergaarde 1, J. Royds 1, R. A. Lothe 1, C. B. Diep 1, G. I. Meling 1, J. Ostrowski 1, L. Trzeciak 1, K. Guzinska-Ustymowicz 1, B. Zalewski 1, G. M. Capellá 1, V. Moreno 1, M. A. Peinado 1, C. Lönnroth 1, K. Lundholm 1, X. F. Sun 1, A. Jansson 1, H. Bouzourene 1, L.-L. Hsieh 1, R. Tang 1, D. R. Smith 1, T. G. Allen-Mersh 1, Z. A. J. Khan 1, A. J. Shorthouse 1, M. L. Silverman 1, S. Kato 1, and C. Ishioka 1

1 Università di Palermo, Department of Oncology, Palermo, Italy

* To whom correspondence should be addressed.
B. Iacopetta, E-mail: bjiac{at}meddent.uwa.edu.au


  Abstract

Background: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (≤20% of wildtype transactivation ability) had different prognostic and 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 classified according to functional status for transactivation.

Results: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability.

Conclusions: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

Keywords: chemotherapy; colorectal cancer; mutation; prognosis; TP53; transactivational ability.
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