GRM1 gene fusions as an alternative molecular driver in blue nevi and related melanomas.

Activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4 genes are regarded as the main oncogenic drivers of blue nevi (BN) and blue malignant melanocytic tumors. Here we report four cases of blue melanocytic neoplasms devoid of these mutations but harboring GRM1 gene fusions. In this short series, there was no gender predominance (sex ratio = 1). The mean age at diagnosis was 40 years (range: 12-72). Tumors were located on the face (n=2), forearm (n=1) and dorsum of the foot (n=1). Clinically, a plaque-like pre-existing blue nevus was found in 2 cases, including a deep location; another case presented as an Ota nevus. Two cases were diagnosed as melanoma ex-blue nevus, one as an atypical BN, and one as a plaque-like BN. Microscopic examination revealed a dermal proliferation of dendritic melanocytes in a sclerotic stroma. A dermal cellular nodule with atypia and mitotic activity was observed in three cases. Genetic investigation by whole-exome RNA sequencing revealed MYO10::GRM1 (n=2) and ZEB2::GRM1 (n=1) fusions. A GRM1-rearrangement was identified by FISH in the remaining case. SF3B1 co-mutations were present in the two melanomas, which both had a MYO10::GRM1 fusion. Array-CGH was feasible for three cases and displayed multiple copy number alterations (CNAs) in the two melanomas and limited CNAs in the atypical BN, all genomic profiles being compatible with those of classical blue lesions. GRM1 was overexpressed in all cases compared to a control group of blue lesions with other typical mutations. Both melanomas rapidly developed visceral metastases following diagnosis, with a fatal outcome in one case and tumor progression under palliative care in the other case. This data suggests that GRM1 gene fusions could represent an additional rare oncogenic driver in the setting of blue nevi, mutually exclusive of classical canonical mutations, especially in plaque-type or Ota subtypes.