BRAF/NRAS wild-type melanomas have a high mutation load correlating with histological and molecular signatures of UV damage

Menée sur 34 échantillons tumoraux et échantillons de sang périphérique prélevés sur des patients atteints d'un mélanome cutané, cette étude met en évidence, pour les tumeurs dont les gènes BRAF et NRAS ne sont pas mutés, un taux élevé de mutations en association avec des lésions provoquées par une exposition aux rayonnements ultra-violets

Résumé en anglais

Purpose: The mutation load in melanoma is generally high compared to other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinico-pathologic features.

Experimental Design: DNA was extracted from 34 fresh frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was performed and mutation rates were correlated with age, sex and tumor site and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation and BRAF/NRAS mutational status were investigated.

Results:The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared to 3.8 per Mb in non-SSD skin (p=0.001). BRAF/NRAS wild-type tumors had a higher average mutation rate compared to BRAF/NRAS mutant tumors (27 versus 5.6 mutations per Mb; p=0.0001). Tandem CC>TT/GG>AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (p=0.0008) and in BRAF/NRAS wild-type tumors (p=0.0007). Targetable and potentially targetable mutations in wild-type tumors, including NF1, KIT and NOTCH1, were spread over various signaling pathways.

Conclusions: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared to BRAF-mutant and NRAS-mutant tumors indicating multi-gene screening approaches and combination therapies may be required for management of these patients.