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 (<i>PTCH1</i>, <i>SMO</i>, <i>GLI1</i>, <i>TP53</i>, <i>CSMD1/2</i>, <i>NOTCH1/2</i>, <i>ITIH2</i>, <i>DPP10</i>, and <i>STEAP4</i>). 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 <i>SMO</i>, <i>PTCH1</i>, <i>TP53</i>, and <i>NOTCH2</i> 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 <i>CSMD1</i>, <i>PTCH1</i>, and <i>NOTCH1</i>, suggesting a UV-independent mechanism. Novel mutations in <i>TAS1R2</i> and <i>ADCY10</i> were exclusive to non-exposed BCCs, with protein-protein interaction analysis linking them to <i>TP53</i> and <i>NOTCH2</i>. We found unique ethnic-specific and UV-independent mutational profiles of BCCs in Koreans. <i>TAS1R2</i> and <i>ADCY10</i> may contribute to tumorigenesis of BCC in non-exposed areas, supporting the need for population-specific precision oncology.