Ethnic-Specific and UV-Independent Mutational Signatures of Basal Cell Carcinoma in Koreans

Basal cell carcinoma (BCC), the most common skin cancer, is primarily driven by Hedgehog (Hh) and TP53 pathway alterations. Although additional pathways were implicated, the mutational landscape in Asian populations, particularly Koreans, remains underexplored. We performed whole-exome sequencing of BCC tumor tissues from Korean patients and analyzed mutations in 11 established BCC driver genes (PTCH1, SMO, GLI1, TP53, CSMD1/2, NOTCH1/2, ITIH2, DPP10, and STEAP4). Mutational profiles were compared with Caucasian cohort profiles to identify ethnicity-specific variants. Ultraviolet (UV)-exposed and non-UV-exposed tumor sites were compared; genes unique to non-UV-exposed tumors were further analyzed with protein-protein interaction analysis. BCCs in Koreans exhibited distinct features, including fewer truncating and more intronic variants compared to Caucasians. Korean-specific mutations in SMO, PTCH1, TP53, and NOTCH2 overlapped with oncogenic gain-of-function/loss-of-function (GOF/LOF) variants annotated in OncoKB, with some occurring at hotspot sites. BCCs in non-exposed areas showed recurrent mutations in CSMD1, PTCH1, and NOTCH1, suggesting a UV-independent mechanism. Novel mutations in TAS1R2 and ADCY10 were exclusive to non-exposed BCCs, with protein-protein interaction analysis linking them to TP53 and NOTCH2. We found unique ethnic-specific and UV-independent mutational profiles of BCCs in Koreans. TAS1R2 and ADCY10 may contribute to tumorigenesis of BCC in non-exposed areas, supporting the need for population-specific precision oncology.