V600E Mutation Has Variable Tumor-Specific Effects on Expression of MAPK Pathway Genes That Could Affect Patient Outcome.

BRAF inhibitors have a 50-70% response rate in melanoma but are less effective for thyroid cancer. Differential response may be from activation or expression of downstream mitogen-activated protein kinase (MAPK) pathway genes. Retrospective analysis compared whole exome and transcriptome sequencing in melanoma and thyroid cancers from April 2019 to October 2023. The MAPK Activation Score (MPAS) was calculated using Z-score normalized/log-transformed values indicating expression across 10 MAPK-associated genes. Our tumor registry provided outcome data. V600E mutations were identified in 33 of 200 (17%) melanomas and 14 (7%) had other mutations (V600K/R). Of 49 thyroid tumor samples, V600E mutations were found in 19 (39%). RNA expression of BRAF and the 10 MAPK-associated genes were increased in melanomas with V600E compared to wild-type ( = 0.02). Conversely, V600E mutation in thyroid cancer was not associated with increased expression nor MAPK pathway activation. No significant difference in overall survival based on mutation was observed in the subset of patients where data was available. The MAPK pathway is differentially affected by the different cancers, with increased MAPK activation observed in melanoma and not in thyroid cancer. This may account in part for the observed differential response to BRAF inhibitors.