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Primary Mucosal Melanomas of the Head and Neck are Characterized by Overexpression of the DNA Mutating Enzyme APOBEC3B.

AIMS
Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behavior and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B-related mutations are identified through C-to-T/-G base substitutions in 5'-TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs.


METHODS AND RESULTS
A3B protein levels were assessed in oral (N=13) and sinonasal (N=13) melanomas, and oral melanocytic nevi (N=13) by immunohistochemistry using a custom rabbit α-A3B mAb (5210-87-13). Heterogeneous, selective-to-diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H-score range=9-72, median=40) and 8 of 13 (62%) sinonasal melanomas (H-score range=1-110, median=24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (p<0.0001 and p=0.0022, respectively), which were A3B-negative (H-score range=1-8, median=4). A3B levels, however, did not differ significantly between oral and sinonasal tumors (p>0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available WGS data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n=2).


CONCLUSIONS
The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis but not benign melanocytic neoplasms.