1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

Basal cell carcinoma (BCC) is the most common skin cancer in white populations with an increasing incidence worldwide, thereby imposing an important public health problem. Its etiology is still unclear, but existing data indicate that the risk for BCC development is of multifactorial origin and results from the interplay of both constitutional and environmental factors. Yet, UV radiation (UVR) is believed to be the predominant causative risk factor in the pathogenesis of BCC. For years, BCC and squamous cell carcinoma (SCC) have been grouped together as “nonmelanoma skin cancer.” However, it seems that there are considerable biologic differences between BCC and SCC, and thus each type of epithelial cancer should be addressed separately. The present review provides an overview of the intriguing etiologic link of BCC with UVR and attempts a comprehensive review of recent epidemiologic and molecular evidence that supports this association.


  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

Basal cell carcinoma (BCC) was first described in 1824 by Jacob (1). Based on immunohistochemical studies, it is defined as a malignant tumor of follicular germinative cells (trichoblasts) (2). It accounts for 75% of all skin cancers and is the most common malignant tumor in white populations (3,4). For years, BCC and squamous cell carcinoma (SCC) have been grouped together as “nonmelanoma skin cancer” (NMSC). However, it seems that there are considerable biologic differences between BCC and SCC, and thus an attempt should be made to address each form of skin cancer separately.

Rates of BCC have been reported to be increasing in many countries around the world, and predictions from the Netherlands suggest that its incidence will continue to increase until at least 2015 (5–11). The average lifetime risk for white-skinned individuals to develop BCC is approximately 30% (12,13). Mortality rates are low, but BCC may occasionally grow aggressively causing extensive tissue destruction (14). Its frequency of metastatic dissemination is very low (<0.1%), but cases of metastases to lymph nodes, lung, bone and liver have been described (15,16).

A latency period of 20–50 years is typically observed between the time of UV damage and the clinical onset of BCC. BCC most commonly occurs in adults, especially in the elderly population, although it rarely may be seen in adults younger than 50 years old (17). BCC is more common in men than in women with a male-to-female ratio of approximately 2:1. Interestingly, women younger than 40 years of age have been found to slightly outnumber men in this age group (7,11,18). The increased incidence rates could be attributed to changes in sunbathing behavior in the young and the middle-aged, which has changed during the 20th century. Particularly after the Second World War, more people had leisure time for outdoor activities. Also, women’s clothing changed allowing larger parts of the body to be exposed to the sun (7). The rate of BCC has tripled in the past 30 years, thereby posing an important health problem with a considerable cost for its management. Moreover, the management of a patient with skin cancer demands a multidisciplinary approach including dermatologists, plastic surgeons, pathologists, oncologists and radiologists (8,11,19).

The etiology of BCC is still unclear but appears to be of multifactorial origin, resulting from a complex interaction of both intrinsic and extrinsic factors (Table 1). UV radiation (UVR), and especially UVB, is responsible for the majority of cutaneous damage and is believed to be the primary established risk factor in the development of BCC (20,21). Other extrinsic risk factors, beyond UVR, predisposing to BCC, include ingestion of arsenic acid (medicine, pesticides), ionizing radiation, X-ray and grenz-ray exposure, topical nitrogen mustard administration and thermal burns. Constitutional factors include gender, age, immunosuppression and genetic predisposition (a family history of BCC, genetically inherited nucleotide excision repair [NER] defects such as xeroderma pigmentosum [XP]). Also, pigmentary traits, such as fair skin, blond or red hair, light eye color, tendency to sunburn and poor tanning ability (skin Type I), have all been associated with a higher risk of BCC (22).

Table 1.   Risk factors implicated in sporadic BCC pathogenesis.
Environmental risk factorsIntrinsic factors
  1. BCC = basal cell carcinoma; UVR = UV radiation.

UVRAge >60 years
ImmunosuppressionMale sex
Chemical carcinogens: ingestion of arsenic acid (medicine, pesticides), hydrocarbons, industrial oils, dyes, solventsCutaneous pigmentation: skin Type I
Therapeutic and occupational radiationPositive BCC family history
Thermal burns, scarring (from lupus vulgaris, combustions)Genetic diseases: xeroderma pigmentosum, albinism, Gorlin syndrome
Topical nitrogen mustard 
Viral carcinogenesis 

The present review provides an overview of predisposing factors associated with sporadic BCC pathogenesis, with a focus on the role of constitutional pigmentary characteristics, patterns of UVR exposure, sun exposure in different periods of life and sun protection measures (Fig. 1).


Figure 1.  Complex interplay of factors implicated in sporadic basal cell carcinoma (BCC) pathogenesis.

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BCC epidemiology: the role of latitude

  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

The epidemiology of BCC is difficult to describe accurately for various reasons. Routine recording of BCC is often not performed by cancer registries because of the large number of cases. Also, not all BCC cases are sent for histopathologic verification of diagnosis (23). Evidence on the relationship between sun exposure and skin cancer is largely derived from the consistent variations in BCC incidence in relation to ambient solar irradiance and ethnic characteristics (23). The annual incidence of BCC depends on the geographic region and correlates with the amount of average annual UVR; the closer white-skinned individuals (male or female) live to the equator (higher UV irradiance), the greater is their risk of developing BCC (24–27).

The highest incidence of BCC has been reported in Australia with rates ranging between 1% and 2% per year, followed by the United States and Europe. In Finland, the incidence rates are the lowest compared with other European countries (5,28–33). Special surveys have been conducted in particular populations, but incidence rates vary considerably even within the same population. A report from the Netherlands showed that the annual incidence of BCC was 2.4% in men and 3.9% in women (10). A study in Scotland yielded a crude annual incidence rate of BCC for both sexes combined of 163.8 per 100 000, compared with an estimate of 89.0 per 100 000 for the same period of 1995–1997 in another Scottish study (34,35) This discrepancy may be attributed to the fact that registering only the initial BCC per individual, and not the subsequent ones, may result in underestimating the true incidence of the disease (34). For the period 1993–1998, the Trentino Skin Cancer Registry in Italy calculated an incidence rate of 88 per 100 000 people for BCC (36). In Northern Ireland, for the period 1993–2002, the mean annual male and female age-standardized incidences for BCC were 94 and 72 per 100 000, respectively (11). Rates of NMSC have been reported to be increasing in many countries around the world, as a result of the increasing longevity of the general population, sun exposure behaviors and the depleting ozone layer (5–11).

Migration studies of light-skinned individuals migrating from areas of low, to high, ambient solar irradiance, in comparison with ethnically similar populations born in the high-irradiance areas, have generally been consistent with an effect of sun exposure on skin cancer incidence (23). Migration has as a result that individuals may receive more intense and greater cumulative sun exposure than their genetic evolution has allowed for (37). Also, persons born in the high UV insolation environment of Australia have an increased risk of developing skin cancer compared with those born in Northern Europe who migrated at age 10 years or older (24). Moreover, the risk of BCC decreased with increasing age at arrival in Australia, in a case–control study (38). Thus, sun exposure early in life appears to have a greater influence on subsequent skin cancer development compared with exposures at a later age.

BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?

  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

Solar radiation has been regarded as a major risk factor for NMSC in humans since 1896 when Unna described the skin changes which ended in skin cancer among sailors exposed to the sun (39,40). It was long believed that risk of NMSC was related solely to the cumulative dose of UVR. This stemmed from limited epidemiologic studies showing that the incidence of NMSC is high on chronically sun-exposed body sites and is related to occupational sun exposure (23,41,42). In a case–control study of 213 BCC patients vs 411 controls in Germany, occupational UV exposure was a risk factor (OR 3.6) for BCC development (43).

However, most epidemiologic studies on BCC suggest that—unlike SCC which is directly associated with cumulative sun exposure—the association between BCC and the amount or timing of personal sun exposure appears to be more complex. In the Maryland watermen study, high cumulative UVB exposure was associated with SCC but not BCC (44) and a case–control study of 166 BCC patients vs 158 controls in Italy did not find an association of BCC with a history of outdoor work (45).

Indeed, the relation between UVR and BCC remains highly controversial with regard to patterns of sun exposure and timing of exposures in different periods of life. The role of recreational or “intermittent” sun exposure during childhood or teenage years (periods that are supposed to be critical for tumor development) appears to be of particular importance and has been shown to be a strong risk factor for BCC. The infrequent, intense and intermittent sun exposure during childhood and adolescence, especially before the age of 20, increases the risk of BCC more than if a similar dose was delivered more continuously over the same time period (46). A case–control study of 166 BCC patients vs 158 controls in Italy showed a definite association of BCC with recreational sun exposure during childhood and adolescence and a strong relation with family history of skin cancer (45). This suggests that genetic predisposition and early, intense and intermittent exposure patterns to UVR are key independent risk factors for the development of BCC (43,45).

Also, sunburns that largely represent a biologic effect of intermittent high-dose UV exposure have a positive and independent association with the risk of BCC, both in terms of intensity and number (43,47). Ease of sunburning was significantly associated with BCC (3,45,46,48–52). Studies suggest that childhood sun exposure patterns, particularly in susceptible individuals (nontanners), are important in accounting for adult risk of BCC as they play a major role in the risk of BCC (3,53). On this basis, it has been suggested that BCC might share similar risk factors with cutaneous melanoma (43,45,46,48,50).

The anatomic areas that skin cancer develops on appear to be somewhat related to the average amount of UV exposure to those sites (54). The density of BCC is highest on the sites that are constantly exposed to UV, namely, the head and neck (55). In this context, the distribution of BCC consists of little variation between the sexes for first-ever BCC, with around 70% of cases arising on the head and neck (23,43,56). However, there is an increase in the incidence of BCC on the trunk, with approximately 20% of BCC occurring in less sun-exposed skin sites, a finding that highlights the role of intermittent sunlight exposure in BCC pathogenesis (38,51,57). Of note, histologic subtypes of BCC appear to have a differential localization, with nodular BCC presenting more often on the head and neck and superficial on the trunk (58–60). BCC of the trunk (which are usually of the superficial type) typically affect younger patients (47,59). This finding is probably caused by behavioral changes in sun exposure patterns in young individuals, especially after the Second World War, when more leisure time could be spent for outdoor activities (7). Also, truncal BCC in young women has been associated with a high socioeconomic status, probably due to more frequent travel overseas, more opportunities for intermittent sun exposure as well as better health awareness that prompts to seeking medical advice, in this group (61). Male patients more commonly develop BCC on the trunk, while women develop BCC on the lower limb, a finding that reflects differences in clothing and sun exposure (59,62). Also, there are molecular distinctions depending on the site of BCC development, with BCC on the head and neck more commonly overexpressing the p53 gene (63). Thus, it has been suggested that head and truncal BCC may not share the same etiologic factors, and that BCCs should be analyzed separately according to their anatomic site and histologic type (59,64). Studies that have addressed BCC separately according to the site of development have shown that BCC of the head was associated with fair skin and presence of telangiectasia on the face, whereas BCC of the trunk was more strongly associated with sunburns and presence of solar lentigines on the back, i.e. small, tan, dark brown or black, lesions, located mostly on sun-exposed areas. Both subtypes were associated with an increased number of solar keratoses (65). Increased risk of nodular, but not superficial BCC, has been reported in association with occupational sun exposure, in an Italian case–control study. Also, there was increased risk of head/neck, but not truncal, BCC with occupational sun exposure (47).

Moreover, a strong association has been shown between BCC and skin lesions that are “objective” markers of cumulative sun exposure (whether long-term or intense intermittent), such as actinic keratoses and solar lentigines, which result from a combined effect of sun exposure and skin pigmentation characteristics (3,38,43,45,65).

However, the few analytical studies conducted so far to investigate constitutional and environmental risk factors for BCC have not elucidated the relative importance of these factors, and their results are often inconsistent. These differences may be accounted for by several factors, such as major differences in study design, assessment of exposure and data analysis (3,38,66,67). Also, many measures of skin pigmentation and skin sensitivity to sunlight are self-reported, are subject to recall bias, and could result in a misclassification of cases and controls in risk categories. Recall bias may arise in subjects who are asked to recall childhood and lifetime sun-exposure patterns after many years, but remember only parts of their past history. In addition, patients may not clearly define their sun sensitivity and may not be able to clearly distinguish their burning tendency from their tanning ability (45).

In conclusion, although UVR exposure is a critical predisposing risk factor for the development of BCC, it cannot singlehandedly explain the development of BCC on an individual basis (Table 2). The complex association of UV exposure and BCC is further highlighted by existing controversial data on the role of photochemotherapy with oral psoralen and UVA irradiation (PUVA) and BCC (5).

Table 2.   Data that highlight the complex association of UVR with BCC occurrence.
  1. UVR=UV radiation; BCC = basal cell carcinoma; PUVA = psoralen and UVA irradiation.

20% of BCC arise on nonsun-exposed skin (e.g. trunk)
Exposure to UV during childhood and adolescence is critical for BCC development
Higher risk for individuals with skin Type I: fair skin, blond or red hair and light-colored eyes, susceptible to sunburn
Higher risk for intense intermittent amount of sun exposure when compared with an equal dose of continuous exposure
Protective role of skin pigmentation
Controversial evidence on PUVA and BCC risk

Basic concepts on UVR-associated BCC pathogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

The sun emits UVR that is subdivided into UVA (320–400 nm), UVB (290–320 nm) and UVC (200–290 nm). More than 95% of the solar UVR that reaches the earth’s surface is UVA, 1–5% is UVB, whereas most UVC is absorbed by the ozone layer and oxygen in the atmosphere and is thus a very small source of adverse human health effects (68). UVR especially prior to the age of 20 years is suggested to initiate a process of basal cell carcinogenesis (69). UVR has two major effects that influence BCC development, namely DNA damage and immunosuppression (70). While UVA has historically been implicated in skin aging (photoaging), it has now been linked, along with UVB, in the development of cutaneous immunosuppression and skin cancer (photocarcinogenesis) (68). However, UVA and UVB damage DNA through different mechanisms, with UVB radiation believed to play a greater role in BCC development than UVA. As the depth of penetration into the skin is dependent on the wavelength, UVB is largely absorbed by epidermal cellular components (proteins, DNA), while UVA radiation penetrates deeply into the basal layer of the epidermis and dermal fibroblasts (71–73).

An extensive review of UVR effects on the skin is beyond the scope of this article, so a brief mention of UVR effects linked with BCC development, namely immunosuppression, creation of reactive oxygen species (ROS) and gene mutagenesis, will follow.

UVR-induced immunosuppression and inflammation linked with BCC development

UVR induces immunosuppression, which, to some degree, is dose-dependent. It modifies the cellular immune mechanisms by depletion of epidermal dendritic Langerhans cells (CD1a+), by altering the lymphocytic antigen-presenting ability, and the expression of immunosuppressive cytokine such as interleukin (IL)-4, IL-10, IL-3, IL-6, IL-8, and tumor necrosis factor-α (51,56,74). This results in a change from T helper type-1 to T helper type-2 response thereby inhibiting the ability of antigen presenting cells to induce antitumor immunity. It also seems that the presence of IL-10 in BCC is directly or indirectly responsible for the complete lack of expression of human leukocyte antigen (HLA)-DR, intercellular adhesion molecule (ICAM)-1 CD40 and CD80 and may be a way of escaping immune surveillance (75).

UVB is a major environmental carcinogen that has been implicated in the development of BCC (21). Exposure to UVB is initially associated with an inflammatory response characterized by increased blood flow and vascular permeability which results in edema and erythema, the infiltration of neutrophils into the dermis, the induction of pro-inflammatory cytokines and the production of ROS (21,76). It is now clear that inflammatory cells such as neutrophils can be powerful tumor promoters. Neutrophils and other phagocytic cells induce DNA damage in proliferating cells through their generation of reactive oxygen and nitrogen species, which are normally produced by these cells against infections (77). In addition, these cells mediate damage through the generation of arachidonic acid derivatives, including prostaglandins and leukotrienes, which are capable of producing an intense inflammatory response (78). These prostaglandins are now believed to contribute to the damage associated with the UVB-induced inflammatory response in the skin. As a byproduct of prostaglandin synthesis, ROS are formed that can induce the formation of oxidative DNA adducts such as 8-oxo-deoxyguanosine (8-oxo-Dg). 8-oxo-dG has been associated with UVB-induced skin carcinogenesis (SCC and sarcoma) in mice (79,80). Recent studies also suggest that reactive intermediates such as those produced following UVB exposures may also contribute to the mutation of genes such as p53, a tumor-suppressor gene that has been shown to play an important role in the multistep UV-induced tumorigenesis. Therefore, an increase in PGE2 production and function appears to be critical to the observed damaging effects of UVB light on the skin (21,81).

Unlike UVB, UVA must first react with non-DNA chromophores in the skin, such as melanin to create ROS and UVA-mediated DNA damage occurs indirectly via oxidative stress. Singlet oxygen and other ROS react with guanine and generate several DNA changes, including mutagenic 7,8-dihydro-8-oxoguanosine (8-oxoG). Recently, it was shown that cyclobutane pyrimidine dimers (CPDs) are the predominant lesion in the DNA damage induced by UVA, supporting a similar-to-UVB mode of mutagenic action (82).

Also, the use of ubiquitously expressing β-act-photolyase mice allows the investigation of the extent that UV-induced DNA lesions affect the immune system by removing either CPDs or 6-4PPs in a light-dependent way. It has been reported that the elimination of CPDs selectively from basal keratinocytes in the mouse skin resulted in significant protection from SCC (83,84). Removal of CPDs (in contrast to 6-4PPs) from the mouse skin abrogates UV-mediated immunosuppression, suggesting a direct effect of CPDs on immunosuppression (83).

Genes implicated in sporadic BCC development and the role of UVR

The skin is the most exposed organ to environmental UV and its associated sequelae. Skin exposure to UVR results in clearly demonstrable mutagenic effects. Especially UVB radiation seems to cause oncogenic mutations in the DNA of keratinocytes leading to BCC (85). DNA and RNA contain strongly absorbing chromophores for UVB. After exposure to UVB, covalent bonds in DNA are induced, generating photoproducts such as CPDs that lead to thymine dimer formation (T/T), and pyrimidine (6-4) pyrimidone lesions (6-4PP) which are mutagenic if left unrepaired. CPDs account for 85% of C–T transitions and pyrimidine photoproducts account for 10–30% of C–T transitions (70). Thymine dimers, if left uncorrected by NER, may affect genes that regulate cellular function, may lead to suppression of the immune response and may interfere with the rejection of the UV-induced mutated cells (86). The role of UVA in mutagenesis is still unclear. CPDs play a central role in UVA-induced mutagenesis, as UVA may induce CPDs (TT, TC, CT CPDs) as a major promutagenic DNA photoproduct, in cultured cells and in whole human skin (82,87). Also, UVA has been shown to induce p53 mutations in basal keratinocytes of engineered human skin (88). A recent study in humans showed that BCC patients are more susceptible to UV-induced DNA damage, as shown by a greater number of CPD-positive cells after UV irradiation, compared to controls (89).

Of note, animal studies have shown than in a nucleotide excision-proficient background UV-induced CPD photolesions are the prime cause of skin carcinogenesis in mice, with respect to SCC or sarcomas, but not BCC (79,84,90,91). These findings highlight the biologic differences in the molecular pathogenesis of SCC and BCC, and the possible protective role of NER proficiency in BCC pathogenesis.

Several genes have been shown to be affected by the C–T transition “imprint” of UVB. Genetic alterations include mutations in the p53 and patched (PTCH) tumor suppressor genes, with up to 50% of the BCC in Caucasian patients showing this mutation in the p53 gene (92). In BCC, other targets for C–T transitions seem to include the smoothened (SMO) gene on chromosome 7q32 (SMO mutations found in 20% of sporadic BCC) (93,94) and the ras proto-oncogene (44).

The p53 tumor suppressor gene, which is frequently mutated in skin cancers, is believed to be an early target of the UVR-induced neoplasm (95–97). The p53 gene encodes a phosphoprotein that regulates cell-cycle control and the maintenance of chromosomal stability. In response to cellular stress, e.g. DNA damage, p53 results in growth arrest, senescence or apoptosis (68). Following UV irradiation, keratinocyte apoptosis in the skin is an important tumor suppressor function of p53. Inactivation of p53 occurs mainly by point mutation of one allele, followed by loss of the remaining wild-type allele (98–100). P53 could influence BCC pathogenesis through its ability to regulate the physiologic tanning response, which is modulated by the transcriptional induction of the proopiomelanocortin (POMC) gene (POMC, alpha-melanocyte stimulating hormone [α-MSH], melanocortin 1 receptor [MC1R], microphthalmia transcription factor cascade) via a mechanism which appears to occur within keratinocytes (101,102).

Moreover, signature C–T transitions have been found in the homolog of the Drosophila gene PTCH1 (9q22.3) (70,103,104). The PTCH1 gene is the genetic defect of Gorlin’s syndrome, but mutations in the PTCH gene have also been found in 30–40% of sporadic BCC (105). Also, UV irradiation enhances BCC occurrence in PTCH1 mutant mice (106). The PTCH1 gene product is part of a receptor for a protein called Sonic Hedgehog, which is involved in embryonic development (14). As the Sonic Hedgehog signaling pathway is essential for hair follicle morphogenesis, BCC—when associated with PTCH1 mutations—might represent uncontrolled hair follicle morphogenesis (14). An orally bioavailable systemic Hedgehog signaling pathway inhibitor is being evaluated for the treatment of BCC in human clinical trials (107,108).

A familial tendency to develop BCC is well documented in several hereditary syndromes, including XP and basal cell nevus syndrome, in which a defective DNA repair mechanism of UVR-induced damage and inactivating mutations of the PTCH gene (a gene involved in a signaling pathway required for correct embryonic development), respectively, underlie the clinical manifestations (45,109). XP is a rare autosomal recessive disease, characterized by defective NER. The NER is a repair system to remove a variety of bulky, helix-distorting lesions. A mutation of the XP gene group A through G, which is involved in NER, results in a protein product incapable of repairing UV-induced photoproducts (CPDs, pyrimidines). Consequently, XP patients have a >1000-fold increased risk of UVR-induced skin cancer, with a much earlier age at onset (110). Other evidence implicating the failure of DNA repair in BCC formation comes from the fact that application of T4 endonuclease, an enzyme that recognizes and cleaves CPDs, leads to a decrease in BCC in XP patients (111).

BCC risk, pigmentary characteristics and the role of gene polymorphisms

  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

An important determinant of skin cancer risk is the cutaneous pigmentation and the tanning ability in response to UVR exposure. The protective role of pigmentation is underlined by the low BCC occurrence in patients of ethnicity with more intensely pigmented skin (112–114). The rate is 19 times less in dark-skinned races than in white-skinned individuals. Among African individuals with lighter skin BCC develop in the same frequency as described for Caucasians, while Africans suffering from albinism develop BCC at an early age (115). A limited number of studies have addressed the association of pigmentary characteristics with BCC risk (Table 3). High-risk patients are often fair-skinned with a history of sun burning and poor tanning ability (3,43). The only two large prospective studies exploring risk factors for BCC in a cohort of female nurses (116) and in a cohort of male physicians (50) in the United States showed that red or light hair color, light eye color, north European ancestry, tendency to sunburn and the number of severe sunburns were all associated with an elevated risk of BCC.

Table 3.   Statistically significant associations of recreational vs occupational sun exposure and phenotypic traits, with BCC risks found in published studies.
AuthorsType of study, patient numberRelative risk (RR), odds ratio (OR) of BCC by pigmentary traits and patterns of sun exposure
  1. BCC = basal cell carcinoma.

Hunter et al. (116)Prospective study USA, = 73 366Red hair, RR = 2.45 Tendency to sunburn, painful sunburns: independent markers of increased risk
Kricker et al. (38)Case–control study Australia, = 226Poor tanning ability, RR = 2.2 Heavy freckling on the arms, RR = 1.6 >4 moles (≥5 mm) on the back, RR = 1.8 Severe solar elastosis of the neck, RR = 3.96
Kricker et al. (46)Case–control study Australia, = 4103Risk increased strongly with increasing intermittency of sun exposure at 15–19 years of age (P for trend = 0.01) History of sunburn, RR = 1.75
Gallagher et al. (3)Case–control study Canada, = 226Freckling, RR = 1.8
Lear et al. (52)Case–control study UK, = 827Skin Type I, RR = 2.36 Light eye and hair color, RR = 1.61
Lock-Andersen et al. (67)Case–control study Danish, = 145No association with hair, eye or skin color
Van Dam et al. (50)Prospective study USA, = 3273Red hair, RR = 1.46 Red/blond hair/hazel/green/blue eyes/tendency to sunburn, RR = 3.08 Tendency to painfully sunburn, RR = 2.13 >10 sunburns, RR = 1.69
Corona et al. (45)Case–control study Italy, = 166Actinic keratoses, RR = 3.2 Solar lentigines, RR = 1.7 Number of weeks/year summer beach holidays, before the age of 20 years, RR = 1.8–4.5
Walther et al. (43)Case–control study Germany, = 213Red/fair hair color, RR = 4.3 History of sunburn, RR = 3.6 Actinic keratoses, RR = 2.7 Solar lentigines, RR = 2.5 Actinic cheilitis, RR = 7.1 Occupational UV exposure, RR = 2.4
Pelucchi et al. (47)Case–control study Italy, = 528Severe sunburn (OR = 3.40) Nodular BCC associated with:  Occupational sun exposure (OR = 1.53) Head/neck BCC associated with:  Occupational sun exposure (OR = 1.46)  Light eyes (OR = 2.31)
Neale et al. (65)Prospective study Australia, = 373Head BCC associated with fair skin (OR = 1.64) and telangiectasia of the face (OR = 2.06) Truncal BCC associated with sunburns (OR = 1.79) and solar lentigines on the back (OR = 3.47) Solar keratoses (OR = 2.43–3.18)

Indeed, the susceptibility for BCC seems to be largely defined by pigmentary characteristics that dictate the cutaneous response to UVR and are controlled by a number of genes or gene variants (Table 4) (117).

Table 4.   Genes implicated in BCC development.
GeneGene function
  1. BCC = basal cell carcinoma.

MC1R, ASIP, TYR, OCA2Pigment regulation
p53 codon 72Apoptosis
Glutathione-S-transferase (GST)Chemical detoxification
HLA-DR4, IL-10 TNF-haplotype a2b4d5Immune function

It has been suggested that NMSC on sun-protected anatomic sites may occur in individuals with decreased DNA repair capacity (62,118). Glutathione-S-transferase (GST) detoxifies DNA and lipid products of oxidative stress, and thus inherited polymorphisms within the GST family of genes may predispose to BCC (119). Also, the xeroderma pigmentosum group D (XPD) gene encodes a helicase, that participates in both NER and basal transcription as part of the transcription factor TFIIH (120). Mutations that influence the enzymatic function of XPD protein are manifested clinically in various syndromes including XP (121). In healthy individuals, the XPD protein level may also be important, as the mRNA level of XPD has been shown to correlate with the DNA repair capacity in primary lymphoblasts (122). Polymorphisms in the NER gene XPD gene (codon 156 of exon 6, codon 751 of exon 23 or codon 312 of exon 10) have been associated with increased risk of BCC (123,124). The A23G polymorphism in the xeroderma pigmentosum group A (XPA) gene, which is also necessary for NER, has been associated with an increased risk of BCC (110).

The melanocortin 1 receptor (MC1R) gene (chromosome 16q24.3) is one of the identified genes that accounts for phenotypic variation in human pigmentation (hair color, skin color and tanning ability) (125). Other pigmentation genes include tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), human Type II oculocutaneous albinism-related gene (OCA2), SLC24A5, SLC45A2, pro-opiomelanocortin (POMC), agouti signaling protein (ASIP) and attractin (ATRN) (126,127). However, very few variants of these genes have been studied in relation to BCC risk.

MC1R is highly polymorphic and allelic variants are responsible for physiologic skin color differences in healthy individuals (128). MC1R is expressed on melanocytes and regulates the synthesis of eumelanin via binding of α-melanocyte-stimulating hormone (α-MSH). A clear dosage effect regarding MC1R variants has been reported, with heterozygotes tending to be intermediate between homozygotes and wild-type individuals for skin type (including tanning ability), freckling and shade of hair (126,129). Furthermore, polymorphisms of the MC1R gene have been associated with increased risk of melanoma and NMSC (130,131). It has been shown that melanocytes with a nonfunctional MC1R (due to loss-of-function mutations) demonstrate in vitro an increase in their sensitivity to the cytotoxic effects of UVR (132).

In a controlled study of 15 single nucleotide polymorphisms (SNPs) in eight pigmentation genes (TYR, TYRP1, OCA2, SLC24A5, SLC45A2, POMC, ASIP and ATRN), only SNPs in the OCA2 and the ASIP gene were associated with BCC risk (127).

In another study, the effect of variants at various pigmentation genes was assessed on BCC risk in European populations, and variants at the ASIP and TYR loci were associated with BCC. Interestingly, not all genetic variants underlying pigmentation traits confer detectable risk of BCC (133).

Also, the common p53 codon 72 polymorphism alters the protein’s transcriptional activity, which may influence the UVR-induced tanning response. However, a study of the interaction of the p53 codon 72 polymorphism with MC1R variants on tanning response and skin cancer risk did not show such an interaction for BCC (134).

In addition, recent data show a possible significant association of the vitamin D receptor polymorphisms FokI and BsmI with NMSC risk, opening the way for future research (135).

Effect of sun protection strategies on BCC development

  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

As skin cancer is linked to excessive sun exposure, a simple behavioral change lowering UV exposure can also lower subsequent skin cancer risk (136,137). For individuals who have a tendency to burn in the sun, active protective measures must be taken throughout life. The same holds true for XP patients, also called children of the dark. This would lead to a containment of the increase or even a reduction in NMSC incidence, as has been demonstrated in Australia (18). Also, persons with a history of BCC had fewer subsequent BCCs developed if they protected themselves from UV exposure (138).

Moreover, the worldwide increase in BCC incidence underscores the need for a public health policy for NMSC. The “typical” BCC patients in northwestern Europe are becoming younger, and are more often female with tumors arising more often on nonchronically exposed sites, a fact that suggests the role of increased intermittent overexposure to UVR. Furthermore, it has been shown that BCC incidence rates in women exhibited a cohort effect, with continuously increasing rates in younger birth cohorts. This suggests that behavioral risk factors will have an increasing influence over successive generations. Public campaigns targeted at young women are needed, with an aim to diminish related risk behaviors such as sun exposure and tanning (7).

Studies have shown that broad-spectrum sunscreens (with UVB and UVA protection) provide better protection from UV-induced neoplasia (139). Also, the use of a high sun protection factor index sunscreen protected against the development of skin tumors in XPA gene knockout mice (140). Regular use of sunscreens during the first 18 years of life has been predicted to reduce the lifetime risk of NMSC by 78% (53). On the other hand, when examining BCC separately, a recent 24-month, prospective, case–control study in immunosuppressed individuals (organ transplant patients) showed that the regular use of sunscreens (as part of sun avoidance measures) did not result in a statistically significant reduction in BCC development (141). Similarly, other analytical studies have shown that the frequent use of sunscreens did not have a statistically significant protective effect after adjusting for age, sex, pigmentary traits, outdoor work, recreational sun exposure before the age of 20 years and family history of skin cancer (45,46).


  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

Epidemiologic evidence relevant to the effects of UVR on BCC risk has been largely indirect, as it was based on the anatomic site of skin cancer development, place or latitude of residence, changes in BCC incidence with migration and the apparent protective effect of constitutive pigmentation. Well-designed epidemiologic studies linking sun exposure and skin cancer directly in individuals are still relatively few (23,142).

The incidence rates of BCC are increasing each year. These trends may be due to increases in both acute and prolonged sun exposure (due to altered life style and pro-tanning behavior), and the depletion of stratospheric ozone, together with the increasing aging of the general population (37). Similar to melanoma and in contrast to SCC, sporadic BCC may occur in individuals with intermittent extreme UV exposure behavior (46,66). With the increased focus on skin cancer prevention strategies, growing interest and attention is being paid to the pathogenesis of skin cancer. The epidemiologic association of UV exposure with the development of BCC is clear; however, there is still much to be learned about its molecular pathogenesis and the role of UVR. For basic research, future work should be aimed at elucidating further the complex genetic and phenotypic risk factors implicated in skin carcinogenesis.

Authors’ biography

  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References

Clio Dessinioti completed her 3-year residency at the Department of Dermatology of the University of Athens, in Andreas Sygros Hospital, Athens, Greece, where she works as a clinical/research fellow since 2007. Dr. Dessinioti is member of various professional societies, including the European Academy of Dermatology and Venereology (EADV), the Hellenic Society of Dermatology and Venereology, and the European Society of Pediatric Dermatology. She has co-authored a book on current therapies, and has been invited as a speaker in national and international meetings. She has participated as sub-investigator in five multicenter clinical trials. Dr. Dessinioti’s research interests include skin cancer, photocarcinogenesis, acne and psoriasis. Her current PhD thesis focuses on the genetic susceptibility of patients with BCC.

Christina Antoniou is a Professor of Dermatology at the University of Athens Medical School, Andreas Sygros Hospital, Athens, Greece. Professor Antoniou’s research interests led to the establishment of the photodermatoses, psoriasis and T-cell lymphoma clinics at Andreas Sygros Hospital. She is a supervisor at the phototherapy department. She has been a principal investigator and has worked extensively on several Phase III studies, mostly with biologic agents for psoriasis. She has written more than 100 articles in peer-reviewed journals, and been a visiting professor and invited speaker at many national and international conferences. Professor Antoniou is a member of various professional societies, including the European Academy of Dermatology and Venereology, American Academy of Dermatology, International Society of Dermatology (ISD), Women’s Dermatology Society and the Hellenic Dermatologic and Venereology.

Andreas Katsambas is Professor and Chairman of the Department of Dermatology and Venereology at the Andreas Sygros Hospital, University of Athens in Greece. He is the Editorial Board member of many international medical journals and the author of more than 180 peer-reviewed published manuscripts. Prof. Katsambas has also co-edited two books, which have since been translated into Greek, Italian and Russian. He is a Board member of the International League of Dermatological Societies (ILDS) and Chairman of the ILDS Awards Committee, as well as the member and honorary member of many international dermatologic societies. Professor Katsambas is a long-standing member of the European Academy of Dermatology and Venereology (EADV), in which he served as Secretary General from 1992 to 2000 and is now EADV President.

Alexander J. Stratigos is an Associate Professor of Dermatology-Venereology at the University of Athens Medical School. Dr. Stratigos is a member of the Board in several Greek and international societies, including the European Academy of Dermatology-Venereology (EADV), the European Society of Cutaneous Lupus Erythematosus (ESCLE) and the Hellenic Society of Melanoma Research. He has published over 80 original and review articles in international peer-reviewed journals and co-authored a book on pediatric dermatology. He is a member of the editorial board in two international scientific journals. Since 2003 he is directing the Pigmented Lesion and Melanoma Unit of Andreas Sygros Hospital (Athens) and in 2007 he established the Photobiology Laboratory in the same Hospital. He has been the principal investigator or co-investigator in five research programs and has participated in eight multicenter clinical trials. His research interests include the epidemiology and molecular epidemiology of melanoma and skin cancer, photocarcinogenesis and cutaneous photosensitivity disorders.


  1. Top of page
  2. Abstract
  3. Introduction
  4. BCC epidemiology: the role of latitude
  5. BCC is due to intermittent (recreational) or chronic (occupational) sun exposure?
  6. Basic concepts on UVR-associated BCC pathogenesis
  7. BCC risk, pigmentary characteristics and the role of gene polymorphisms
  8. Effect of sun protection strategies on BCC development
  9. Conclusions
  10. Authors’ biography
  11. References
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