Specific Mutations inKRASCodons 12 and 13, and Patient Prognosis in 1075BRAFWild-Type Colorectal Cancers

Abstract

Purpose To assess prognostic roles of various KRAS oncogene mutations in colorectal cancer, BRAF mutation status must be controlled for because BRAF mutation is associated with poor prognosis, and almost all BRAF mutants are present among KRAS-wild-type tumors. Taking into account experimental data supporting a greater oncogenic effect of codon 12 mutations compared to codon 13 mutations, we hypothesized that KRAS codon 12 mutated colorectal cancers might behave more aggressively than KRAS-wild-type tumors and codon 13 mutants. Experimental design Utilizing molecular pathological epidemiology database of 1261 rectal and colon cancers, we examined clinical outcome and tumor biomarkers of KRAS codon 12 and 13 mutations in 1075 BRAF-wild-type cancers (i.e., controlling for BRAF status). Cox proportional hazards model was used to compute mortality hazard ratio (HR), adjusting for potential confounders, including stage, PIK3CA mutations, microsatellite instability, CpG island methylator phenotype, and LINE-1 methylation. Results Compared to patients with KRAS-wild-type/BRAF-wild-type cancers (N=635), those with KRAS codon 12 mutations (N=332) experienced significantly higher colorectal cancer-specific mortality [log-rank P=0.0001; multivariate HR=1.30; 95% confidence interval (CI), 1.02–1.67; P=0.037], whereas KRAS codon 13 mutated cases (N=108) were not significantly associated with prognosis. Among the seven most common KRAS mutations, c.35G>T (p.G12V; N=93) was associated with significantly higher colorectal cancer-specific mortality (log-rank P=0.0007; multivariate HR=2.00, 95% CI, 1.38–2.90, P=0.0003) compared to KRAS-wild-type/BRAF-wild-type cases. Conclusions KRAS codon 12 mutations (in particular, c.35G>T), but not codon 13 mutations, are associated with inferior survival in BRAF-wild-type colorectal cancer. Our data highlight the importance of accurate molecular characterization in colorectal cancer.

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

“…This finding is different from Imamura et al, 17 who recently reported an association between poor survival and KRAS codon 12 mutation in BRAF wild-type colorectal carcinoma patients. With multiple studies showing different effects of KRAS mutation on patient survival, it is likely that various confounders may interact and that KRAS mutation does not represent on its own an important prognostic factor in patients with colorectal carcinoma.…”

“…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.…”

Mutación del gen KRAS en el cáncer de colon y recto

“…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.…”

Desenlaces del manejo no quirúrgico posterior a neoadyuvancia del cáncer localmente avanzado de recto

“…Aunque esten aún en investigación y no sea clara su significacia como factores pronósticos, la determinación de marcadores inmunohistoquímicos como p53, Ki67 y moleculares como Kras podrian correlacionarse con el comportamiento del tumor y la respuesta a los tratamientos sobre él [42][43][44][45][46][47][48][49][50] . En un reporte de Lin et al 46 , los autores comparan la expresión de p53, p27 y bcl-2 antes y después de la terapia neoadyuvante, mostrando un incremento de p27 y bcl-2 en los especímenes resecados, al compararse con la biopsia inicial, considerándose que la positividad de p27 parece mejorar el pronóstico.…”