Basal cell carcinoma (BCC) is the most common human malignancy. Although the absolute majority of BCCs are sporadic, its hereditary forms majorly contribute to our understanding of molecular changes underlying BCC onset.
Bazex-Dupré-Christol syndrome (BDCS) is a rare entity with an X-linked dominant inheritance pattern, characterized by triad of hypotrichosis, follicular atrophoderma and early onset BCC. It is caused by loss of function mutations in ACTRTJ gene, which encodes Actin-related protein 1 (ARP-T1). Here, I report ARP-T1 as a ciliary protein found at the base of the primary cilium (PC) in keratinocytes. I show that decrease in ARP-Tl protein expression results in shortened PC, which was confirmed by overexpression ofits mutant form, found in human samples. Assessment of ARP­ Tl interacting partners Mxl, EHD4 and BAG2 in this work establishes an important connection between innate immunity, cellular trafficking and ciliogenesis. Unexpectedly, I identified interferon-induced protein Mxl as a ciliary protein, whose knock-down also results in shortened PC. ARP-Tl plays a role in the regulation of ciliary length, potentially through modulation of the Mxl-mediated apical cargo delivery at the ciliary base. Whole exome sequencing ofhuman BDCS samples in this thesis shows that ACTRTJ mutation alone is not sufficient for BCC formation and additional drivers are necessary for tumor initiation.
For the study ofNevoid basal cell carcinoma syndrome in pediatric population, we show that full inactivation of PTCHJ results in development of Basaloid follicular hamartoma (BFH). Unlike BCC, such tumor possesses a very low number of somatic mutations and PTCHI is the only gene affected by an oncogenic event. We postulate BFH to be a benign, yet precursor lesion, which might transform into invasive BCC if additional second hit occurs. Hence, we suggest a close monitoring or direct removal of such lesions.