**Molecular Mechanisms and Biomarkers of Skin Photocarcinogenesis Photocarcinogenesis**

**Molecular Mechanisms and Biomarkers of Skin** 

DOI: 10.5772/intechopen.70879

Adriana T. Lopez, Liang Liu and Larisa Geskin Adriana T. Lopez, Liang Liu and Larisa Geskin Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70879

#### **Abstract**

Skin cancer is the most commonly diagnosed malignancy in the United States and worldwide. While melanoma is the deadliest form of skin cancer, non-melanoma skin cancers, which include basal cell carcinoma and squamous cell carcinoma, are responsible for significant morbidity in millions of Americans each year. While numerous attempts have been made to reduce skin cancer risk factors related to ultraviolet radiation exposure, skin cancer incidence continues to rise. Improved understanding of the molecular pathways underlying skin cancer pathogenesis has led to the investigation of new approaches to skin cancer prevention. In particular, the search for ultraviolet radiation associated biomarkers of skin cancer has become a rapidly expanding and promising area of research. Advances in genetic sequencing have facilitated the discovery of novel biomarkers, which have the potential to profoundly improve patient care. Here we will review the molecular genetics of skin cancer and analyze the existing literature of proposed biomarkers for potential use in skin cancer diagnosis and prevention.

**Keywords:** ultraviolet radiation, UV biomarkers, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, UV signature

#### **1. Introduction**

Skin cancer is the most common type of cancer in the United States and is estimated to affect one in every five Americans [1, 2]. Skin cancer can be classified as either non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), or melanoma skin cancer. The costs associated with the treatment of skin cancer are substantial and has placed a significant burden on the healthcare system. In the United States, it is estimated that the combined medical expenditures for the treatment of all skin cancers cost approximately \$8.1 billion dollars per year [3].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Unlike many other malignancies, skin cancer is largely preventable in the majority of cases. Ultraviolet radiation (UVR) is strongly associated with cutaneous malignancies and is a primary environmental risk factor for the development of all types of skin cancer [4]. While numerous public health initiatives have increased skin cancer awareness, guidelines developed to mitigate the risks associated with UV exposure are not regularly practiced by many Americans and sunburn rates remain high [5]. Furthermore, recreational and indoor tanning still remains popular among certain groups within the population, which leads to excess UVR exposure [6]. Although most associate sunburns with UV overexposure, few recognize that the increase in melanin production from tanning is triggered by direct UVR damage to skin cells [7]. Repeated exposure to intense UVR in the form of sunburn or tanning can result in cumulative damage within skin cells, leading to cell dysregulation. These sun damaged, cancer-prone cells may exist in the skin for years or even decades before becoming visibly apparent in the form of cancerous or precancerous lesions.

more than 58 million Americans and represents the large number of individuals at risk for the future development of NMSC [12]. While genetic factors such as skin type and family history contribute to an individual's risk of development of skin cancer, UVR exposure and age are the leading risk factors in skin cancer pathogenesis. It is estimated that approximately 90% of NMSCs are associated with excessive exposure to UVR and incidence increases with age [13, 14]. Other general risk factors include chronic arsenic exposure, radiation therapy, photosen-

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Basal cell carcinoma is the most common cutaneous malignancy and represents approximately 80% of all NMSCs [16]. BCCs arise secondary to malignant transformation of cells in the basal layer of the epidermis and its appendages. While BCCs can be aggressive and destructive to surrounding tissue, it has low metastatic potential: estimated at only 0.0029– 0.55% [17]. The majority of BCCs arise sporadically and only a small number of cases are inherited, which typically arise within the setting of syndromic disorders such as nevoid basal cell carcinoma syndrome. It is estimated that approximately 70% of BCCs occur on the face and 35% of patients with one BCC will go on to develop another BCC within 5 years [18]. Based on histologic examination, BCC can be classified as nodular, infiltrative, micronodular, superficial, sclerosing, or morpheaform subtypes. Analysis of the histologic growth pattern and cell differentiation is critical as it provides a means to further categorize the lesion as a high or low risk BCC [19]. Infiltrative, sclerosing, morpheaform, and micronodular BCCs are considered high-risk subtypes given the higher likelihood of subclinical spread and more frequent local recurrence [20]. However, patient treatment and prognostication are frequently complicated by the fact that more than 30% of BCCs have a mixed pathology that combines both less aggressive and more aggressive subtypes within the same lesion [21].

Cutaneous squamous cell carcinoma arises due to malignant proliferation of epidermal keratinocytes and is the second most common type of skin cancer. In a 2013 meta-analysis, the number of new SCCs (exclusive of SCC in situ) in the United States was estimated to be between 186,157 and 419,543 cases [22]. While a number of genetic disorders are associated with increased risk of both BCC and SCC, many hereditary syndromes are skewed toward development of cutaneous SCC (**Table 1**) [23]. Actinic keratosis, which results from the proliferation of atypical epidermal keratinocytes, is strongly associated with UV exposure and is considered a precancerous lesion of SCC [24]. Although some have suggested that AKs are also precursors of BCCs, this association is less clear [25]. Most AKs will not progress to SCCs and many will either regress or persist as AKs [26]. While the likelihood of an individual AK progressing to SCC is low, the presence of AKs is a marker of chronic sun damage and indicates an increased risk of NMSC [27, 28]. In general, SCC is considered highly curable and metastasizes in less than 1–5% of cases [29, 30]. Whereas specific subtypes of BCC are associated with higher or lower risk, there is less consensus as to which features best characterize the aggressiveness of cutaneous SCC. Acantholytic, adenosquamous, and desmoplastic

sitizing drugs, certain genetic disorders, and prolonged immunosuppression [15].

**2.1. Basal cell carcinoma**

**2.2. Squamous cell carcinoma**

Various strategies to encourage sun protective practices and interventions to modify sun related behaviors have had limited success. Low compliance with UV protection guidelines, particularly among young adults, has been attributed to various factors including inconvenience of sunscreen application and societal attitudes toward tanned skin as a sign of beauty [5, 8, 9]. In addition, the long delay from the time of UV exposure to carcinogenesis lowers risk perception of UVR as being dangerous [10]. Although primary prevention of skin cancer is ideal and remains core to decreasing disease incidence, patient risk stratification following UV exposure is critical for both early detection of skin cancer and prevention of worsening disease.

Biomarker discovery has come to play an increasingly important role in both disease diagnosis and prevention. The application of biomarker-based tests has led to revolutionary changes in medical screening, diagnosis, and targeted therapies for a variety of cancers [11]. While the use of biomarkers has become incorporated into the standard of care for numerous malignancies, the application of biomarker studies within NMSC has not yet been clearly established. By identifying UV biomarkers of NMSC, patients can be risk stratified to ensure routine skin cancer screening and pointed efforts can be made to encourage timely lifestyle changes.

Here we review the relevant literature regarding skin cancer pathogenesis, molecular genetics, and potential biomarkers for use in NMSC. In addition, we will critically analyze the strengths and limitations of various types of biomarkers and detection methods. Due to the significant differences that exist at the molecular level between the development of melanoma and NMSC, an in-depth discussion of related literature in melanoma research is beyond the scope of this review. As such, this discussion will focus on biomarker discovery and its applicability to NMSC diagnosis and prevention.

### **2. Non-melanoma skin cancers**

Each year in the United States over 5.4 million cases of NMSC are treated in more than 3.3 million people [2]. Actinic keratosis (AK), the most common precancerous lesion, affects more than 58 million Americans and represents the large number of individuals at risk for the future development of NMSC [12]. While genetic factors such as skin type and family history contribute to an individual's risk of development of skin cancer, UVR exposure and age are the leading risk factors in skin cancer pathogenesis. It is estimated that approximately 90% of NMSCs are associated with excessive exposure to UVR and incidence increases with age [13, 14]. Other general risk factors include chronic arsenic exposure, radiation therapy, photosensitizing drugs, certain genetic disorders, and prolonged immunosuppression [15].

#### **2.1. Basal cell carcinoma**

Unlike many other malignancies, skin cancer is largely preventable in the majority of cases. Ultraviolet radiation (UVR) is strongly associated with cutaneous malignancies and is a primary environmental risk factor for the development of all types of skin cancer [4]. While numerous public health initiatives have increased skin cancer awareness, guidelines developed to mitigate the risks associated with UV exposure are not regularly practiced by many Americans and sunburn rates remain high [5]. Furthermore, recreational and indoor tanning still remains popular among certain groups within the population, which leads to excess UVR exposure [6]. Although most associate sunburns with UV overexposure, few recognize that the increase in melanin production from tanning is triggered by direct UVR damage to skin cells [7]. Repeated exposure to intense UVR in the form of sunburn or tanning can result in cumulative damage within skin cells, leading to cell dysregulation. These sun damaged, cancer-prone cells may exist in the skin for years or even decades before becoming visibly

Various strategies to encourage sun protective practices and interventions to modify sun related behaviors have had limited success. Low compliance with UV protection guidelines, particularly among young adults, has been attributed to various factors including inconvenience of sunscreen application and societal attitudes toward tanned skin as a sign of beauty [5, 8, 9]. In addition, the long delay from the time of UV exposure to carcinogenesis lowers risk perception of UVR as being dangerous [10]. Although primary prevention of skin cancer is ideal and remains core to decreasing disease incidence, patient risk stratification following UV exposure is critical for both early detection of skin cancer and prevention of worsening

Biomarker discovery has come to play an increasingly important role in both disease diagnosis and prevention. The application of biomarker-based tests has led to revolutionary changes in medical screening, diagnosis, and targeted therapies for a variety of cancers [11]. While the use of biomarkers has become incorporated into the standard of care for numerous malignancies, the application of biomarker studies within NMSC has not yet been clearly established. By identifying UV biomarkers of NMSC, patients can be risk stratified to ensure routine skin cancer screening and pointed efforts can be made to encourage timely lifestyle changes.

Here we review the relevant literature regarding skin cancer pathogenesis, molecular genetics, and potential biomarkers for use in NMSC. In addition, we will critically analyze the strengths and limitations of various types of biomarkers and detection methods. Due to the significant differences that exist at the molecular level between the development of melanoma and NMSC, an in-depth discussion of related literature in melanoma research is beyond the scope of this review. As such, this discussion will focus on biomarker discovery and its appli-

Each year in the United States over 5.4 million cases of NMSC are treated in more than 3.3 million people [2]. Actinic keratosis (AK), the most common precancerous lesion, affects

apparent in the form of cancerous or precancerous lesions.

176 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

cability to NMSC diagnosis and prevention.

**2. Non-melanoma skin cancers**

disease.

Basal cell carcinoma is the most common cutaneous malignancy and represents approximately 80% of all NMSCs [16]. BCCs arise secondary to malignant transformation of cells in the basal layer of the epidermis and its appendages. While BCCs can be aggressive and destructive to surrounding tissue, it has low metastatic potential: estimated at only 0.0029– 0.55% [17]. The majority of BCCs arise sporadically and only a small number of cases are inherited, which typically arise within the setting of syndromic disorders such as nevoid basal cell carcinoma syndrome. It is estimated that approximately 70% of BCCs occur on the face and 35% of patients with one BCC will go on to develop another BCC within 5 years [18]. Based on histologic examination, BCC can be classified as nodular, infiltrative, micronodular, superficial, sclerosing, or morpheaform subtypes. Analysis of the histologic growth pattern and cell differentiation is critical as it provides a means to further categorize the lesion as a high or low risk BCC [19]. Infiltrative, sclerosing, morpheaform, and micronodular BCCs are considered high-risk subtypes given the higher likelihood of subclinical spread and more frequent local recurrence [20]. However, patient treatment and prognostication are frequently complicated by the fact that more than 30% of BCCs have a mixed pathology that combines both less aggressive and more aggressive subtypes within the same lesion [21].

#### **2.2. Squamous cell carcinoma**

Cutaneous squamous cell carcinoma arises due to malignant proliferation of epidermal keratinocytes and is the second most common type of skin cancer. In a 2013 meta-analysis, the number of new SCCs (exclusive of SCC in situ) in the United States was estimated to be between 186,157 and 419,543 cases [22]. While a number of genetic disorders are associated with increased risk of both BCC and SCC, many hereditary syndromes are skewed toward development of cutaneous SCC (**Table 1**) [23]. Actinic keratosis, which results from the proliferation of atypical epidermal keratinocytes, is strongly associated with UV exposure and is considered a precancerous lesion of SCC [24]. Although some have suggested that AKs are also precursors of BCCs, this association is less clear [25]. Most AKs will not progress to SCCs and many will either regress or persist as AKs [26]. While the likelihood of an individual AK progressing to SCC is low, the presence of AKs is a marker of chronic sun damage and indicates an increased risk of NMSC [27, 28]. In general, SCC is considered highly curable and metastasizes in less than 1–5% of cases [29, 30]. Whereas specific subtypes of BCC are associated with higher or lower risk, there is less consensus as to which features best characterize the aggressiveness of cutaneous SCC. Acantholytic, adenosquamous, and desmoplastic


The wavelength of UVB radiation primarily corresponds to the absorption spectrum of DNA. Upon skin exposure to UVB radiation, electromagnetic energy is absorbed by biologic molecules and transformed into chemical energy [34]. When UV photons are absorbed by DNA molecules, electrons are excited to a high energy state, which can result in formation of photoproducts [37]. The two major DNA lesions induced by UVB radiation are the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs). These lesions are ultimately caused by the misbonding of two pyrimidines, either thymine or cytosine, within the same DNA strand. Both lesions can lead to genetic mutations including C→T and CC→TT transitions; however, CPDs are considered more carcinogenic because they are more prevalent and less efficiently repaired than 6-4PPs [34]. If left unrepaired, these dimers become mutagenic, which highlights the equally important role of the DNA repair system in skin carcinogenesis. Pyrimidine dimers are normally removed by nucleotide excision repair (NER) enzymes. In patients with xeroderma pigmentosum (XP), a disease characterized by defective NER enzymes, individuals exhibit a decreased ability to repair DNA mutations, especially those caused by UVR. In individuals with XP, this clinically manifests as the development of NMSC and melanoma skin cancers at a young age [38]. In building on the knowledge learned from patients with XP, studies have subsequently sought to uncover novel defects in NER enzymes within the general population. It has been suggested that polymorphisms within NER enzymes increase susceptibility to the development of NMSC [39]. While polymorphic variants of DNA repair genes may contribute to an individual's risk of developing NMSC fol-

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lowing UV exposure, it is unclear at this time to the extent by which one is affected.

**4. Molecular mechanisms underlying skin carcinogenesis**

Our understanding of cancer biology and the molecular pathology underlying malignant transformation has grown considerably within the past several decades. In particular, the advent of high-throughput sequencing technologies has enabled the detection of various mutational signatures. Dysregulation of proto-oncogenes and tumor suppressor genes, which

tive pathways that lead to carcinogenesis.

In contrast to UVB, the exact role of UVA in skin carcinogenesis is far more nebulous. Although UVA is partially absorbed by the epidermis, it also penetrates to the dermis where collagen fibers function to scatter light [34]. Until relatively recently, UVA has long been considered to play a minor role in the development of skin cancer as photons of UVA are not within the absorbable wavelength of DNA [34]. However, molecular studies have since illuminated the potentially significant function of UVA in photocarcinogenesis. Recently, research has shown that UVA causes indirect DNA damage via the generation of reactive oxygen species, and DNA-protein crosslinks, as well as direct DNA damage by formation of CPDs or singlestrand DNA breaks [40, 41]. While the role of UVA radiation in the formation of skin cancer is not yet clarified, epidemiologic studies also seem to support its harmful effects. Indoor tanning beds, which primarily emit UVA radiation, have been linked to the increased incidence of skin cancer among users [42, 43]. It has been reported that just one indoor tanning session can increase a user's risk of developing SCC by 67% and BCC by 29% [44]. There is thus compelling evidence to elevate the role of UVA in the formation of skin cancer by perhaps alterna-

**Table 1.** Hereditary syndromes predominantly associated with increased risk of cutaneous SCC.

subtypes are recognized as high risk variants; however, traditionally low risk variants may achieve high risk status based on tumor features including size, location, and lesion depth, which have been independently correlated with SCC risk [31].
