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Cited by 242Nonmelanoma Skin Cancer StudiesHedgehog Signaling Pathway StudiesCancer and Skin Lesions

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Understanding the Molecular Genetics of Basal Cell Carcinoma

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Pellegrini, Cristina, Maturo, Maria, Di Nardo, Lucia, Ciciarelli, Valeria, Gutiérrez García-Rodrigo, Carlota, Fargnoli, Maria·2017·International Journal of Molecular Sciences
DOI 10.3390/ijms18112485PMC PMC5713451
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Abstract

Basal cell carcinoma (BCC) is the most common human cancer and represents a growing public health care problem. Several tumor suppressor genes and proto-oncogenes have been implicated in BCC pathogenesis, including the key components of the Hedgehog pathway, PTCH1 and SMO, the TP53 tumor suppressor, and members of the RAS proto-oncogene family. Aberrant activation of the Hedgehog pathway represents the molecular driver in basal cell carcinoma pathogenesis, with the majority of BCCs carrying somatic point mutations, mainly ultraviolet (UV)-induced, and/or copy-loss of heterozygosis in the PTCH1 gene. Recent advances in sequencing technology allowed genome-scale approaches to mutation discovery, identifying new genes and pathways potentially involved in BCC carcinogenesis. Mutational and functional analysis suggested PTPN14 and LATS1, both effectors of the Hippo–YAP pathway, and MYCN as new BCC-associated genes. In addition, emerging reports identified frequent non-coding mutations within the regulatory promoter sequences of the TERT and DPH3-OXNAD1 genes. Thus, it is clear that a more complex genetic network of cancer-associated genes than previously hypothesized is involved in BCC carcinogenesis, with a potential impact on the development of new molecular targeted therapies. This article reviews established knowledge and new hypotheses regarding the molecular genetics of BCC pathogenesis.

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Crossref · 10.3390/ijms18112485

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Figures

Figure 1 Physiologic and oncogenic Hedgehog signaling. (a) In the absence of HH ligands, PTCH1 constitutively represses SMO, blocking the HH signal transduction; (b) The family of extracellular HH ligands binds to PTCH1, de-represses SMO thereby allowing its translocation on the tip of the primary cilium. SMO sends signals through a series of interacting proteins, including SUFU, resulting in activation of the downstream GLI family of transcription factors; (c) Loss of function of PTCH1 (red cross) or activating mutations of SMO (blue asterisk) induces HH pathway in the absence of HH ligands. HH; Hedgehog; PTCH1; Patched Homolog 1; SMO; SMOothened; SUFU; suppressor of fused; GLI; glioma-associated oncogene.
Figure 1 Physiologic and oncogenic Hedgehog signaling. (a) In the absence of HH ligands, PTCH1 constitutively represses SMO, blocking the HH signal transduction; (b) The family of extracellular HH ligands binds to PTCH1, de-represses SMO thereby allowing its translocation on the tip of the primary cilium. SMO sends signals through a series of interacting proteins, including SUFU, resulting in activation of the downstream GLI family of transcription factors; (c) Loss of function of PTCH1 (red cross) or activating mutations of SMO (blue asterisk) induces HH pathway in the absence of HH ligands. HH; Hedgehog; PTCH1; Patched Homolog 1; SMO; SMOothened; SUFU; suppressor of fused; GLI; glioma-associated oncogene.CC BY · PubMed Central
Figure 2 Hippo–YAP pathway. When the Hippo pathway is activated, MST1/2 kinases and SAV1 form a complex to phosphorylate and activate LATS1/2 and MOB1. Activated LATS1/2 phosphorylates YAP/TAZ, that is sequestered in the cytoplasm or degraded. Dephosphorylation of YAP/TAZ allows its traslocation into the nucleus and the interaction with TEAD1-4 to induce the expression of genes promoting tumor progression. MST, mammalian Ste2-like kinases Hpo orthologs; SAV, Protein Salvador Homolog 1; LATS, Large Tumor Suppressor Kinase Wts orthologs; MOB1, Mob-as-tumor-suppressor homologs; YAP, Yes Associated Protein Yki ortholog; TEAD, transcriptional enhancer associate domain; TAZ, transcriptional co-activator with PDZ-binding motif; SMAD, Mothers against decapentaplegic homolog.
Figure 2 Hippo–YAP pathway. When the Hippo pathway is activated, MST1/2 kinases and SAV1 form a complex to phosphorylate and activate LATS1/2 and MOB1. Activated LATS1/2 phosphorylates YAP/TAZ, that is sequestered in the cytoplasm or degraded. Dephosphorylation of YAP/TAZ allows its traslocation into the nucleus and the interaction with TEAD1-4 to induce the expression of genes promoting tumor progression. MST, mammalian Ste2-like kinases Hpo orthologs; SAV, Protein Salvador Homolog 1; LATS, Large Tumor Suppressor Kinase Wts orthologs; MOB1, Mob-as-tumor-suppressor homologs; YAP, Yes Associated Protein Yki ortholog; TEAD, transcriptional enhancer associate domain; TAZ, transcriptional co-activator with PDZ-binding motif; SMAD, Mothers against decapentaplegic homolog.CC BY · PubMed Central
Figure 3 Schematic representation of TERT promoter structure. TERT promoter region (red bar) and TERT gene (pink bar). Core consensus sequence with Ets/TCF regulatory elements of TERT promoter and location of BCC-specific mutations (red) are reported in the box. The Ets/TCF binding motifs for Ets/TCF transcription factors created by mutations are underlined. TERT, telomerase reverse transcriptase; Ets/TCF; Ternary complex factor (TCF) subgroup of the Ets E26 transformation-specific transcription factor.
Figure 3 Schematic representation of TERT promoter structure. TERT promoter region (red bar) and TERT gene (pink bar). Core consensus sequence with Ets/TCF regulatory elements of TERT promoter and location of BCC-specific mutations (red) are reported in the box. The Ets/TCF binding motifs for Ets/TCF transcription factors created by mutations are underlined. TERT, telomerase reverse transcriptase; Ets/TCF; Ternary complex factor (TCF) subgroup of the Ets E26 transformation-specific transcription factor.CC BY · PubMed Central

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Research works printed but not linked: 2

  1. White, 1894, Multiple benign cystic epitheliomas, J. Cutan. Genitourin. Dis., 12, 477
  2. Jarisch, 1894, On the doctrine of skin tumors, Arch. Dermatol. Syphilol., 18, 162

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Metadata

Authors
Pellegrini, C., Maturo, M., Di Nardo, L., Ciciarelli, V., Gutiérrez García-Rodrigo, C., & Fargnoli, M.
Affiliations
  • University of L'Aquila (IT)
  • Department of Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy
Corresponding author
Fargnoli, Maria
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2017-11-22
Volume
18
Issue
11
Pages
2485
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms18112485
PMC
PMC5713451
OpenAlex
W2770311193
Cited by
242
References
123
Citations by year
2026: 15 · 2025: 22 · 2024: 25 · 2023: 27 · 2022: 41 · 2021: 46 · 2020: 37 · 2019: 20 · 2018: 8
FWCI
2.35
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion, public-domain)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Dermatology › Nonmelanoma Skin Cancer Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Dermatology › Cancer and Skin Lesions
Keywords
basal cell carcinoma, tumor suppressor, proto-oncogenes, Hedgehog signaling, PTCH1, SMO, TP53, Ras family, UV-induced mutations, PTPN14, LATS1, Hippo signaling pathway, MYCN, TERT promoter mutation, carcinogenesis, targeted therapy
MeSH terms
Proto-Oncogene Mas, Animals, Basal Cell Carcinoma, Cell Transformation, Neoplastic, Humans, Mutation, Skin Neoplasms, Genetic Therapy, Signal Transduction, Biomarkers, Gene Expression Regulation, Neoplastic, Loss of Heterozygosity, Genetic Predisposition to Disease

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