Aims: Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour 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 tumours (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 whole-genome sequencing (WGS) data disclosed that the number of C-to-T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2). Conclusion: The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms.
Bibliographical noteFunding Information:
We thank Brian Dunnette for sharing expertise regarding the use of the Aperio ScanScope XT and Ashley Gunderson and Alexandra Blixt, University of Minnesota Oral Pathology Laboratory, for assistance with specimen procurement and clinical information collection. These studies were supported by P01‐CA234228 (to RSH). Salary support for MCJ was provided in part by T32‐CA009138 and subsequently F31‐CA243306. Salary support for JN was provided in part by T32‐DA007097. RSH is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute.
© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.
- DNA cytosine deamination
- oral mucosal melanoma
- sinonasal mucosal melanoma
PubMed: MeSH publication types
- Journal Article