Intra-patient Heterogeneity of BRAF and NRAS Molecular Alterations in Primary Melanoma and Metastases
Cristina Pellegrini, Ludovica Cardelli, Marina De Padova, Lucia Di Nardo, Valeria Ciciarelli, Tea Rocco, Gianluca Cipolloni, Marco Clementi, Alessio Cortellini, Alessandra Ventura, Pietro Leocata, Maria Concetta Fargnoli
Mutations in MAPK signalling genes are driver events in melanoma, and have therapeutic relevance in the metastatic and adjuvant setting. This study evaluated the intra-patient heterogeneity of BRAF, NRAS and c-KIT mutational status between 30 primary melanomas and 39 related metastases, using molecular analysis and immunohistochemistry. BRAF mutations were identified in 46.7% of primary melanomas and 48.7% of metastases and NRAS mutations in 20% and 25.6%, respectively. Intra-patient heterogeneity was detected in 13.3% of patients for both BRAF and NRAS genes and was not associated with clinico-pathological characteristics of melanomas or metastases. High consistency was observed between immunostaining and molecular methods for BRAFV600E (k = 0.90; p < 0.001) and NRASQ61R (k = 0.87; p < 0.001). These findings demonstrate a relevant intra-patient heterogeneity between primary and metastatic lesions that is independent of clinical variables and methodological approach.
Cutaneous melanoma is one of the most aggressive and treatment-resistant tumours. Intra-patient concordance of mutations in genes, such as BRAF, NRAS and c-KIT, between primary melanoma and related metastases is a critical aspect that has become even more relevant with the introduction of therapies targeting specific mutations. This study evaluated the intra-patient heterogeneity of BRAF, NRAS and c-KIT mutational status in 30 primary melanomas and 39 related metastases, using molecular analysis and immunohistochemistry. Clinically meaningful intra-patient heterogeneity was found between primary melanoma and related metastases, independent of the technical approach, thus supporting the polyclonal model of melanoma progression.