Integrative genetic and transcriptomic analyses reveal alternative carcinogenetic pathways in basal cell carcinoma

Basal cell carcinoma (BCC), the most common form of skin cancer, is primarily driven by mutations in genes of the Hedgehog signaling pathway. However, most BCCs also harbor mutations in non-Hedgehog genes, whose contributions to tumorigenesis remain poorly understood. Here, we introduce a novel computational approach that integrates whole-exome sequencing and RNA-sequencing data to systematically link somatic mutations with downstream transcriptional alterations in BCC. Using matched tumor and normal skin samples from 25 BCC patients, we quantified gene expression fold changes and assessed how these fold changes differed between patients harboring or lacking specific gene mutations. Our analysis identified 15 mutated genes significantly associated with distinct expression changes in 345 genes, which clustered into four functional modules. Mutations in KCNQ3 , NAV3 , ADAMTSL1 , and SAMD3 were linked to up-regulation of immune-suppressive genes that may impair CD8 + T cell function. SRRM4 mutations were connected with aberrant splicing in 14 genes enriched in cilium assembly, while mutations in IFT122 , along with seven mutated genes, resulted in more down-regulations of 20 ribosomal protein genes, potentially affecting cilia assembly. Concurrent mutations of ZBP1 and CAMKK1 , regulating innate immunity and calcium signaling, were correlated with reduced expression of genes involved in innate immune response and keratinocyte differentiation. Collectively, our findings highlight additional genetic contributors and pathways in BCC pathogenesis, revealing potential molecular links between immune suppression, calcium signaling, and tumor development. This integrative approach provides a foundation for mechanistic studies and the development of personalized therapeutic strategies for BCC.