RAS/ BRAF molecular profile in metastatic versus non-metastatic colorectal cancer

RAS and BRAF genes are crucial therapeutic and prognostic markers in metastatic colorectal cancer. Once activated, these oncogenes play a key role in colorectal carcinogenesis from the beginning steps until metastasis development. Several hotspot mutations were described in the KRAS and the NRAS genes and codon 600 of the BRAF gene. Herein, we were interested in RAS/BRAF mutation profiles in metastatic colorectal cancer compared to non-metastatic tumors.

We screened for RAS/BRAF hotspot mutations byt he Idylla IVD mutation test for KRAS and NRAS-BRAF, in a series of 810 colorectal cancer patients (CCR) which were distributed as follow: 492 patients had lymph nodes or distant metastases at diagnosis, and 318 without any metastases.

RAS/BRAF mutation screening showed no difference in KRAS*distribution between metastatic and non-metastatic colorectal patients (49.6%vs 49.0% respectively), but NRAS* and BRAF* were more frequent in metastatic CCR (4.7% and 4.3% vs 2.8% for NRAS* and BRAF*in non-metastatic CCR). Moreover, detailed analysis of KRAS codon mutations revealed that G12 mutations were more recurrent in metastasis than in non-metastasis CCR (71% and 65% respectively) while, G13D mutation was more frequent in non-metastatic CCR (20% vs 13% in metastatic cancer). Finally, we noted that the rare mutation G12R was correlated with non-metastatic cancer (3% vs 0.6% in mCCR).The distribution of RAS/BRAF mutations in metastatic lymph nodes compared to distant metastasis showed a higher frequency of KRAS* in distant metastasis group (52.0% vs 43.6%), no difference was noted for the NRAS*/BRAF* distributions. Alleles’ distribution of KRAS* highlighted a higher frequency of codons 12 and 13 in lymph node metastasis (respectively 73.4% and 11.4% vs 67.6% and 9% in distant metastases), and more codon 61* was associated with distant metastasis cancer (8.1% vs 3.8%). More detailed, the G12A and G12S alleles were associated with distant metastasis (12.2% vs 5.2% and 8.1% vs 1.7%) while G12D and G12V were associated with lymph node metastasis (43.1% vs 39.2% and 36.2% vs 28.4%). However, we did not notice any difference in organ metastasis site distribution with the molecular profile of the RAS/BRAF genes.

Our results highlighted a difference in the molecular profile of KRAS, NRAS,and BRAF mutations’ distribution between metastatic colorectal cancer and non-metastatic ones: NRAS and BRAF mutations were associated with metastasis advent; moreover, the G13D mutation of KRAS was correlated to a better prognosis than mutations in codon 12 of KRAS: G12A and G12S alleles gave the worst prognosis.

The authors.

Has not received any funding.

All authors have declared no conflicts of interest.