Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study

H J N Andreyev, A R Norman, D Cunningham, J Oates, B R Dix, B J Iacopetta, J Young, T Walsh, R Ward, N Hawkins, M Beranek, P Jandik, R Benamouzig, E Jullian, P Laurent-Puig, S Olschwang, O Muller, I Hoffmann, H M Rabes, C Zietz, C Troungos, C Valavanis, S T Yuen, J W C Ho, C T Croke, D P O’Donoghue, W Giaretti, A Rapallo, A Russo, V Bazan, M Tanaka, K Omura, T Azuma, T Ohkusa, T Fujimori, Y Ono, M Pauly, C Faber, R Glaesener, A F P M de Goeij, J W Arends, S N Andersen, T Lövig, J Breivik, G Gaudernack, O P F Clausen, P De Angelis, G I Meling, T O Rognum, R Smith, H-S Goh, A Font, R Rosell, X F Sun, H Zhang, J Benhattar, L Losi, J Q Lee, S T Wang, P A Clarke, S Bell, P Quirke, V J Bubb, J Piris, N R Cruickshank, D Morton, J C Fox, F Al-Mulla, N Lees, C N Hall, D Snary, K Wilkinson, D Dillon, J Costa, V E Pricolo, S D Finkelstein, J S Thebo, A J Senagore, S A Halter, S Wadler, S Malik, K Krtolica, N Urosevic

Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.