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

Abstract

SummaryResearchers 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 incolorectal-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. © 2001 Cancer Research Campaign http://www.bjcancer.comIt is widely accepted that mutations in the Kirsten ras (Ki-ras) gene in patients with colorectal cancer develop early in the progression from adenoma to carcinoma. Our first collaborative study including 2721 patients, clarified that Ki-ras mutations are not only 692

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

“…Oncogenic activation of RAS signaling pathways has been implicated in many aspects of the malignant process, including abnormal cell growth, proliferation, and differentiation. KRAS mutations are, in most cases, an early event in the development and progression of colorectal cancers [56,58,59]. Consistent with this concept, several studies have demonstrated that KRAS mutation status is an important prognostic factor in colorectal cancer [55,[58][59][60].…”

“…Consistent with this concept, several studies have demonstrated that KRAS mutation status is an important prognostic factor in colorectal cancer [55,[58][59][60]. KRAS mutations are associated with tumors of more advanced stage, increased metastatic potential, poor prognosis, and decreased PFS and OS of patients [55,56,58,59]. The prognostic value of KRAS mutations in colorectal cancer is presently controversial and warrants further confirmation.…”

“…However, these alterations account for a minor proportion (1-4%) of KRAS mutations and their clinical relevance in colorectal cancer is unclear [51,53]. KRAS mutations in codons 12 and 13 appear to play a major role in the progression of colorectal cancer [54][55][56], while mutations in codons 12, 13, and 61 are potential biomarkers in lung cancer [57].…”

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

“…Our exon 2 KRAS mutation rate of 28% is in agreement with previous studies when mutations in exon 2 only are considered. 10,11,16,17 Like BRAF-mutated carcinomas, KRAS-mutated carcinomas showed an increased frequency of mucinous differentiation. This finding has been previously observed by Lin et al 28 and more recently by Pai et al, 8 who reported that 32% of proximal KRAS-mutated carcinoma showed mucinous differentiation compared with 25% of null carcinomas.…”

“…7,10,11 The overwhelming majority of KRAS mutations (90%) occur in codons 12 and 13 of exon 2, with the most frequent alteration being a G4A transition in codon 12. 12 The clinical significance of KRAS mutation in colorectal carcinoma patients is controversial; some studies reported no association with survival, 13,14 whereas others suggested that patients with KRASmutated colorectal carcinoma have poorer outcome for any mutation subtype, 15 mutation in codon 12 only 16,17 or codon 13 only. 11 There is more definitive evidence for a negative predictive value of KRAS mutation in patients with advanced stage disease treated with targeted anti-EGFR monoclonal antibody drugs.…”