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The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics

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Mutations in the sonic hedgehog signaling pathway play a key role in the development of basal cell carcinomas. Specifically, mutations in the PTCH1 (also known as PTCH or PTC1) and SMO genes cause tumor formation through constitutive activation of the pathway. Misregulation of the pathway has also been implicated in the nevoid basal cell carcinoma syndrome and other tumors. Understanding the function of the sonic hedgehog pathway has led to novel strategies for treatment. In this review we highlight the role of the pathway in the pathogenesis of basal cell carcinoma and review potential targeted therapies.

Introduction

Basal cell carcinoma (BCC) is the most common human malignancy, amounting to 90% of skin cancers. Risk factors for BCC include fair skin type, sun exposure, ionizing radiation, advanced age, immunosuppression, and a personal history of nonmelanoma skin cancer.1 Specifically, ultraviolet (UV) and ionizing radiation can induce DNA damage that leads to the development of skin cancer, and defective DNA repair is associated with advanced age. In addition, studies of long-term immunosuppression after organ transplantation and in patients with chronic lymphocytic leukemia showed increased risks for cancers, particularly nonmelanoma skin cancer. Although the majority of such nonmelanoma cancers are squamous cell carcinomas, an increase in BCCs has also been shown.2

Hereditary predisposition to BCC occurs among individuals with albinism, xeroderma pigmentosum, nevoid basal cell carcinoma syndrome, Rasmussen syndrome, Rombo syndrome, Bazex-Christol-Dupre syndrome, and Darier disease. Occurrence of BCCs in these disorders can be linked to either instability of the skin or diminished pigmentation.1, 3 Although multiple factors contribute to risks for BCC, the underlying mechanism is genetic alteration. Thus analysis of mutations in the sonic hedgehog (SHH) pathway has improved our understanding of the role of the pathway in BCC development.

Section snippets

Sonic hedgehog signaling and tumor development

The mammalian hedgehog family includes the Indian hedgehog (IHH), desert hedgehog (DHH), and sonic hedgehog (SHH) genes. SHH signaling is critical for early embryologic development and is involved in formation of the neural tube, musculoskeletal system, hematopoietic cells, teeth, and skin. For example, mutations in the SHH pathway can cause severe congenital malformations, such as holoprosencephaly, a cyclops-like phenotype. In the skin, the SHH pathway is responsible for maintaining the stem

Summary of sonic hedgehog signaling

The key components of the hedgehog pathway include SHH, PTCH1, SMO, and GLI proteins (Fig 1).12 Briefly, in the absence of SHH, PTCH1 constitutively represses SMO. Binding of SHH to PTCH1 relieves SMO repression, allowing full-length GLI proteins to be imported into the cell nucleus.11 These proteins (GLI1, GLI2, and GLI3) are transcription activators with DNA-binding zinc fingers. Other signals downstream of the SHH pathway include proteins involved in WNT signaling and bone morphogenetic

Sonic hedgehog signaling and BCC pathogenesis

Carcinogenesis is a multiple-step process leading to accumulation of mutations that result in tumor-forming cells. A significant risk factor for BCC development is UV radiation. While UVA plays some role in photocarcinogenesis, UVB induces structural changes in epidermal DNA known as UV signature mutations or UV fingerprints. These mutations are characterized by C to T or CC to TT transitions at dipyrimidine sequences and result from cyclobutane dimer formation.

Patients with nevoid BCC syndrome

Sonic hedgehog signaling and cell proliferation

The sonic hedgehog pathway has been implicated in cell cycle regulation, particularly at the G2/M transition (Fig 2). The G2/M transition is mediated by M-phase promoting factor (MPF), which consists of CDC2 (cell division cycle 2, also known as CDK1) and cyclin B1.18 Normal epithelial cells exit the cell cycle before terminal differentiation, whereas SHH protein activation instead leads to cell proliferation. As a mechanism, PTCH1 protein, when not bound to SHH, normally interacts with cyclin

Sonic hedgehog–directed pharmacologic agents for BCC

As understanding of the SHH pathway and tumorigenesis unfolds, investigations of novel strategies targeting the pathway will be forthcoming. Development of small molecule inhibitors of specific SHH signals may pave the way for new BCC treatments. Brief discussions of targeted therapies and their molecular mechanisms are given in the following paragraphs and in Table I.

Clinical implications

Knowledge of not only the SHH pathway components, but also the downstream molecular effectors of SHH signaling, present opportunities for the development of targeted therapeutics. The runt-related transcription factors lie downstream of the SHH pathway, and skin tumorigenesis has been directly linked to RUNX1 expression, possibly by promoting the proliferation of epithelial cells.47 Therefore, instead of therapeutics targeting SHH, which has important, potential clinical limitations of

Conclusions

The hedgehog pathway is an important regulator of embryologic development and is also involved in tumor formation. Aberrant activation of this pathway leads to increased cell proliferation and subsequent tumors. The connection between BCC pathogenesis and misregulation of the SHH pathway due to inactivating PTCH1 mutations and activating SMO mutations is well documented. Since BCC is the most common human malignancy, a detailed understanding of its pathophysiology is clinically relevant for

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    Funding sources: None.

    Conflicts of interest: None declared.

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