Understanding the Molecular Genetics of Basal Cell Carcinoma

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.

Keywords: DPH3 promoter; LATS1; MYCN; PTCH1; PTPN14; TERT promoter; TP53; basal cell carcinoma; molecular genetics.

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 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 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.