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

Abstract

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.

Somatic Mutations of K-Ras and BRAF in Thai Colorectal Cancer and their Prognostic Value

“…In our study, although the association between K-Ras mutation status and EFS was limited to stage I-III, we found that mutations at codon 12 of K-Ras were significantly associated with poorer EFS in all stages. This finding is consistent with some previous studies that found a prognostic value of codon 12 mutations in CRC (Font et al, 2001;Poehlmann et al, 2007;Winder et al, 2009;Elserafi, 2010). The prognostic value of this specific codon might be explained in a functional study which proved that malignant transformation of NIH3T3 cells by codon 12-mutated K-Ras had a more aggressive phenotype when compared to codon13-mutated K-Ras (Guerrero et al, 2000).…”

Mutación del gen KRAS en el cáncer de colon y recto

“…Nuestros hallazgos muestran la presencia de mutación del gen KRAS en 42% de los cánceres de colon y recto, cifra muy similar a la reportada en los múltiples trabajos publicados en la literatura 32,33,41 . Un hecho similar se observa en relación a la distribución porcentual de los distintos tipos de mutaciones, con sobre 80% de mutaciones del codón 12 y aproximadamente 20% en el codón 13.…”

“…También fue demostrado que la determinación del estado silvestre (no mutado) o mutado del gen KRAS era capaz de predecir la respuesta del tumor al uso de inhibidores del EGRr, siendo su determinación clínicamente útil 13,39,40 . Algunos estudios han demostrado que algunos tipos específicos de mutación de KRAS tienen relación con la sobrevida, como la mutación G12V, la que se asociaría a un pronóstico más adverso de la enfermedad en relación a otros tipos de mutaciones [41][42][43] . A pesar de la importancia y al fácil estudio de la estructura de este gen, no existe información publicada en nuestro medio respecto de la frecuencia y tipo de mutaciones del gen KRAS en Chile en el cáncer de colon y recto, por lo cual, desconocemos no sólo su frecuencia y el tipo de mutaciones presentes en nuestra población, lo cual, pudiese tener importancia terapéutica.…”

Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine

“…We additionally used comparative genomic hybridisation (CGH) analysis to identify common chromosomal aberrations in colorectal tumours, and highlighted an amplification of the region of chromosome 12p where the K-Ras gene is localised (Leslie et al, 2003). We and others have shown that K-Ras mutations are associated with significantly reduced survival in colorectal cancer patients (Andreyev et al, 2001;Conlin et al, 2005), although previous data is not entirely consistent (EtienneGrimaldi et al, 2008;Winder et al, 2009). K-Ras mutation status has recently been convincingly associated with response to the new generation EGFR antagonists cetuximab (Erbitux) and panitumumab (Vectibix), where response is preferentially observed in wt K-Ras tumours (Lievre et al, 2006;Benvenuti et al, 2007;Khambata-Ford et al, 2007;Freeman et al, 2008;Karapetis et al, 2008;Ramos et al, 2008;Loupakis et al, 2009;Van Cutsem et al, 2009).…”