Researchers worldwide with information about the Kirsten ras (Ki-ras) tumou
r genotype and outcome of patients with colorectal cancer were invited to p
rovide that data in a schematized format for inclusion in a collaborative d
atabase called RASCAL (The Kirsten ras in-colorectal-cancer collaborative g
roup). Our results from 2721 such patients have been presented previously a
nd for the first time in any common cancer, showed conclusively that differ
ent gene mutations have different impacts on outcome, even when the mutatio
ns occur at the same site on the genome. To explore the effect of Ki-ras mu
tations at different stages of colorectal cancer, more patients were recrui
ted to the database, which was reanalysed when information on 4268 patients
from 42 centres in 21 countries had been entered. After predetermined excl
usion criteria were applied, data on 3439 patients were entered into a mult
ivariate analysis. This found that of the 12 possible mutations on codons 1
2 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 fa
ilure-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 ea
rly in the development of pre-cancerous adenomas in the colon and rectum. H
owever, 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 pati
ents with advanced colorectal cancer. (C) 2001 Cancer Research Campaign.