KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies
Menée sur des échantillons tumoraux prélevés sur 838 patients atteints d'un cancer colorectal et 1 765 patients atteints d'un cancer du poumon non à petites cellules, cette étude analyse les différences dans les profils de mutations du gène KRAS entre les deux types de cancer
Background : KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and Methods : Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined.≤ABS-P ≥ <ST>Results</ST> KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p < 0.001), smoking-associated G > T transversions (73% versus 27%; p < 0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p < 0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT > TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY > ASP substitutions (resulting in a G > A transition) were more frequent in CRC (42%) compared with NSCLC (21%). Conclusion : In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.