The Contributions of Cancer-Testis and Developmental Genes to the Pathogenesis of Keratinocyte Carcinomas

SIMPLE SUMMARY: In addition to mutations, ectopically-expressed genes are emerging as important contributors to cancer development. Efforts to characterize the expression patterns in cancers of gamete-restricted cancer-testis antigens and developmentally-restricted genes are underway, revealing these genes to be putative biomarkers and therapeutic targets for various malignancies. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are two highly-prevalent non-melanoma skin cancers that result in considerable burden on patients and our health system. To optimize disease prognostication and treatment, it is necessary to further classify the molecular complexity of these malignancies. This review describes the expression patterns and functions of cancer-testis antigens and developmentally-restricted genes in BCC and cSCC tumors. A large number of cancer-testis antigens and developmental genes exhibit substantial expression levels in BCC and cSCC. These genes have been shown to contribute to several aspects of cancer biology, including tumorigenesis, differentiation, invasion and responses to anti-cancer therapy. ABSTRACT: Keratinocyte carcinomas are among the most prevalent malignancies worldwide. Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) are the two cancers recognized as keratinocyte carcinomas. The standard of care for treating these cancers includes surgery and ablative therapies. However, in recent years, targeted therapies (e.g., cetuximab for cSCC and vismodegib/sonidegib for BCC) have been used to treat advanced disease as well as immunotherapy (e.g., cemiplimab). These treatments are expensive and have significant toxicities with objective response rates approaching ~50–65%. Hence, there is a need to dissect the molecular pathogenesis of these cancers to identify novel biomarkers and therapeutic targets to improve disease management. Several cancer-testis antigens (CTA) and developmental genes (including embryonic stem cell factors and fetal genes) are ectopically expressed in BCC and cSCC. When ectopically expressed in malignant tissues, functions of these genes may be recaptured to promote tumorigenesis. CTAs and developmental genes are emerging as important players in the pathogenesis of BCC and cSCC, positioning themselves as attractive candidate biomarkers and therapeutic targets requiring rigorous testing. Herein, we review the current research and offer perspectives on the contributions of CTAs and developmental genes to the pathogenesis of keratinocyte carcinomas.