Genetics
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About 90 per cent of BCC cases are due to inappropriate regulation of the Hedgehog (HH) signaling pathway (Pellegrini, Maturo, Di Nardo, Ciciarelli, García-Rodrigo, & Fargnoli, 2017). HH signaling is involved in the development of skin stem cells and hair follicle and sebaceous glands (Pellegrini et al., 2017). This signaling pathway was first identified in individuals with basal cell nevus syndrome (Gorlin syndrome), which causes a genetic predisposition to BCC, leading to the development of multiple BCC tumors from a young age (Pellegrini et al., 2017). This genetic mutation is located on human chromosome 9q22 (Pellegrini et al., 2017). The majority of cases involve loss-of-function mutations of Patched 1 (PTCH1) gene, which gives rise to transmembrane receptor proteins (Pellegrini et al., 2017). More sporadic cases of BCC (10-20%), which are not related to basal cell nevus syndrome, are affected by gain-of-function mutations of smoothened (SMO) gene, which produce G-protein coupled receptor-like protein SMO and glioma-associated oncogene (GLI), which affects transcription factors (Pellegrini et al., 2017).
Under normal conditions in the cell, PTCH1 represses SMO signaling, which prevents the initiation of the HH signaling pathway (Pellegrini et al., 2017). However, under any one of the following situations, HH signaling can be initiated, supporting tumorigenesis or tumor growth (Pellegrini et al., 2017):
HH signaling activation results from any pathway that gives rise to GLI-mediated transcription of the target gene (Pellegrini et al., 2017).
Source: Pellegrini, C., Maturo, M., Di Nardo, L., Ciciarelli, V., Gutiérrez García-Rodrigo, C., & Fargnoli, M. (2017). Understanding the molecular genetics of basal cell carcinoma. International Journal of Molecular Sciences, 18(11), 2485.
Under normal conditions in the cell, PTCH1 represses SMO signaling, which prevents the initiation of the HH signaling pathway (Pellegrini et al., 2017). However, under any one of the following situations, HH signaling can be initiated, supporting tumorigenesis or tumor growth (Pellegrini et al., 2017):
- binding of extracellular HH ligands (or proteins) to PTCH1, which relieves the repression on SMO, activating downstream signaling;
- loss-of-function mutations to PTCH1, which again relieves the repression on SMO; or
- gain-of-function mutations of SMO, which initiates the HH downstream signaling
HH signaling activation results from any pathway that gives rise to GLI-mediated transcription of the target gene (Pellegrini et al., 2017).
Source: Pellegrini, C., Maturo, M., Di Nardo, L., Ciciarelli, V., Gutiérrez García-Rodrigo, C., & Fargnoli, M. (2017). Understanding the molecular genetics of basal cell carcinoma. International Journal of Molecular Sciences, 18(11), 2485.
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Another important genetic factor in BGG tumorigenesis is the inactivation of the TP53 tumor suppressor gene (Pellegrini et al., 2017). This gene is known as “Guardian of the Genome” and “Policeman of Oncogenes” since the loss of its activity is involved in half of all human cancers (Efeyan & Serrano, 2007). Normally, TP53 is inactive in the cell, rapidly degraded by ubiquitin ligase MDM2, but can be activated by cellular stress, including DNA damage and oncogenic signaling (Efeyan & Serrano, 2007). During activation, ubiquitin ligase MDM2 is halted, allowing TP53 to buildup in levels, leading to the activation of cell cycle inhibitors and pro-apoptotic proteins (Efeyan & Serrano, 2007). UV-induced mutations in TP53 cause CC to TT double base changes, which disables its function in suppressing tumor growth (Pellegrini et al., 2017).
Source: Efeyan, A., & Serrano, M. (2007). p53: guardian of the genome and policeman of the oncogenes. Cell Cycle, 6(9), 1006-1010.
Other genes implicated in BCC development include (Pellegrini et al., 2017):
· Hippo-YAP signaling genes—controls organ size
· MYCN/FBXW7—downstream transcriptional activators of the HH pathway
· TERT-promoter—involved in telomerase activity
· DPH3-OXNAD1 bidirectional promoter—involved in maintenance of translation
· many more…
Source: Efeyan, A., & Serrano, M. (2007). p53: guardian of the genome and policeman of the oncogenes. Cell Cycle, 6(9), 1006-1010.
Other genes implicated in BCC development include (Pellegrini et al., 2017):
· Hippo-YAP signaling genes—controls organ size
· MYCN/FBXW7—downstream transcriptional activators of the HH pathway
· TERT-promoter—involved in telomerase activity
· DPH3-OXNAD1 bidirectional promoter—involved in maintenance of translation
· many more…