Prognostic Significance of Microsatellite Instability and Ki-&lt;i&gt;ras&lt;/i&gt; Mutation Type in Stage II Colorectal Cancer

Wang, Cathy; Rijnsoever, Marius van; Grieu, Fabienne; Bydder, Sean; Elsaleh, Hany; Joseph, David; Harvey, Jennet; Iacopetta, Barry

doi:10.1159/000069311

Cited by 57 publications

(36 citation statements)

References 18 publications

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“…24). This metastasis site-specific association of KRAS may partly explain the heterogeneity seen in previous studies analyzing KRAS mutation status and survival in colorectal cancer patients (37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 84%

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Tie

Lipton

Desai

et al. 2011

Clinical Cancer Research

198

169

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Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse.Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n ¼ 65), lung (n ¼ 50), and brain (n ¼ 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n ¼ 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial.Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P ¼ 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR ¼ 2.1; 95% CI, 1.2 to 3.5, P ¼ 0.007) but not liver relapse in patients from the VICTOR trial.Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies.

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Section: Discussionmentioning

confidence: 84%

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Tie

Lipton

Desai

et al. 2011

Clinical Cancer Research

198

169

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“…However, reported prognostic impact of the K-Ras mutations provided inconsistent results (18)(19)(20)(21)(22). A large meta-analysis suggested that the G12V mutation at codon 12 in the K-Ras gene increases the risks of recurrence or death in patients with colorectal cancer (5).…”

Section: Discussionmentioning

confidence: 99%

Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer

Winder

Mündlein²,

Rhomberg³

et al. 2009

Oncol Rep

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Abstract.A glycine to valine substitution at codon 12 (G12V) in Kirsten-Ras (K-Ras) gene has been associated with reduced overall survival in colorectal cancer patients; however, the effect of other K-Ras mutations than G12V still remains unclear. Therefore, we investigated the role of different K-Ras mutations on overall survival in a homogeneous, large patient cohort with standardized therapy and uniform analysis of K-Ras mutation status. The study included 342 patients with histopathologically proven colorectal cancer. Survival data were provided by the federal agency for statistics in Austria. Occurrence of K-Ras mutations at codons 12, 13 and 61 were determined by capillary sequencing. The overall K-Ras mutation frequency in carcinoma tissue was 28%. Carriers of the G12V mutation at the K-Ras gene showed a significantly decreased overall survival compared to carriers of the wild-type [HR=2.56 (1.15-5.69)]. Other mutations than G12V were associated with better overall survival compared to wild-type [HR=0.44 (0.2-0.99)]. In conclusion, for the first time, our study showed clearly that different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer.

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“…PCR and fluorescent single strand conformation polymorphism analysis were used to screen for hot-spot mutations in the BRAF (V600E) and KRAS (codons 12 and 13) oncogenes and for mutations in exons 5-8 of the TP53 tumour suppressor gene, as described previously by our laboratory. [18][19][20] The hot-spot mutations in BRAF and KRAS were independently confirmed by direct DNA sequencing for a small proportion of samples.…”

Section: Tumour Specimens and Intracellular Folate Measurementsmentioning

confidence: 99%

APC gene methylation is inversely correlated with features of the CpG island methylator phenotype in colorectal cancer

Iacopetta

Grieu

et al. 2006

Intl Journal of Cancer

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The notion of a CpG island methylator phenotype (CIMP) was proposed to describe a subset of colorectal cancers (CRC) displaying frequent and concordant methylation of CpG islands located within gene promoter regions. Some workers have failed to observe associations between CIMP and specific clinicopathological features of CRC, possibly because of the choice of genes used to define this phenotype. The aim of the current study was to determine whether the aberrant methylation of 6 genes implicated in CRC development was associated with the same phenotypic features of this tumour type. The MethyLight assay was used to provide quantitative estimates of MLH1, P16, TIMP3, P14, DAPK and APC methylation levels in 199 unselected colorectal tumours. The methylation of MLH1, P16, TIMP3 and P14 was highly concordant (p < 0.0001 for each pair) but that of DAPK and APC was not. An inverse association was observed between the methylation of APC and TIMP3 (p = 0.004). Methylation of the MLH1, P16, TIMP3 and P14 genes was associated with tumour infiltrating lymphocytes (p < 0.05), microsatellite instability (p < 0.001), BRAF mutation (p < 0.0001) and elevated concentrations of the methyl group carriers tetrahydrofolate (THF) and 5,10-methylene THF (p < 0.05). In contrast, APC methylation was associated with wildtype BRAF (p = 0.003) and with lower concentrations of methyl group carriers (p < 0.05). These findings highlight the importance of gene selection in studies that aim to characterize the biological features and clinical behaviour of CIMP+ tumours.

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Prognostic Significance of Microsatellite Instability and Ki-<i>ras</i> Mutation Type in Stage II Colorectal Cancer

Cited by 57 publications

References 18 publications

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer

APC gene methylation is inversely correlated with features of the CpG island methylator phenotype in colorectal cancer

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