Analysis of Genetics and Environmental Factors in Non-Melanoma Skin Cancer
Non-melanoma skin cancer (NMSCs) predominantly basal cell carcinoma (BCC) and Squamous cell carcinoma (SCC) are the most diagnosed form of cancer worldwide. Several studies have been done to provide a better understanding of the mechanisms that lead to NMSC. Many studies have demonstrated that genetic predisposition together with environmental factors contributes to NMSC development. Pathogenesis of SCC and BCC is associated with several risk factors but the most significant ones are genetic alterations and exposure to ultraviolet radiation. Frequent exposure to UV radiation is associated with DNA damage, immunosuppression, and inflammation which in turn increase the risk for both BCC and SCC. There is considerable variability in the incidence of UV-induced SCC and BCC across age, sex and geographic location. The understanding of the risk factors associated with the NMSC development allows development of effective preventive strategies. Protection against exposure to solar UV radiation has not proven to be effective in reducing NMSCs, and thus agents with chemopreventive effects are needed. Dietary grape-seed proanthocyanidins (GSPs) have proven effective in the reduction of the incidence of NMSCs due to its chemopreventive effects. GSPs prevent inhibits tumor initiation and growth by inhibiting UVB-induced immunosuppression and promoting DNA repair. GSPs reduce the levels of interleukin-10 in a skin that is highly exposed to UV radiation and increases production of interleukin-12 to inhibit immunosuppression. Thus, dietary GSPs is a promising preventive strategy due to its ability to attenuate the adverse effects of UV radiation and inhibit the development of NMSCs.
Keywords: Non-melanoma skin cancer, pathogenesis, DNA damage, DNA repair, Ultraviolet radiation, Inflammation, immunosuppression, proanthocyanidins
Non-melanoma skin cancer (NMSC) is less dangerous cancer as compared to malignant melanoma. Although NMSCs are rarely fatal, they can be a precursor for life-threatening conditions (Wheeler, Kothencz & Polland, p.235). Kim & He (188) note that the incidence of most other malignancies has either declined or stabilized while that of NMSC continues to increase considerably. Moreover, NMSCs accounts for a significant amount of money allocated to the healthcare system. NMSCs account for $ 3 billion annually in the US hence they impose a heavy burden on the healthcare system (Katiyar et al., 138). There are two frequently diagnosed NMSCs: basal cell carcinoma (BCC) and Squamous cell carcinoma (SCC). BCC accounts for 70% of NMSC while SCC accounts for 25%. NMSC show different metastatic capability, growth, and behavior but both SCC and BCC have a good prognosis particularly when detected early. Although BCC shows limited potential for metastasis and lowers degree of malignancy as compared to SCC, it is associated with tissue damage that can result in extensive morbidity. Several individual factors increase the risk for BCC including genetic diseases, immunosuppression, age, and gender. However, a high level of exposure to ultraviolet radiation plays the most significant role in the pathogenesis of BCC (Griewank et al., 1 & Didona et al., 7). SCC has a potential to metastasize which depends on the immune system, perineural invasion, degree of histological differentiation and the size of the tumor (Didona et al., 8). Frequent sun exposure and proliferation of mutated genes are significant risk factors for SCC.
The prevalence and incidence for both SCC and BCC continue to increase at an alarming rate. NMSCs are the most diagnosed malignancies and accounts for 40% of new cases of cancers in the US (Katiyar et al., 138). Over the last two decades, the prevalence of SCC and BCC increased by 133% and 35% respectively (Didona et al., 7). The incidence of BCC is 2.75 million worldwide representing a significant public health issue (Pellegrini et al., 2485). Therefore, NMSC is a significant issue hence preventive strategies should be developed to reduce its burden.
The study examines the pathogenesis of NMSC and evaluates possible preventive methods to reduce the health and financial burden of these malignancies. A comprehensive review will be done to investigate how both genetics and environmental factors contribute to the pathogenesis of NMSCs. Lastly, the paper presents prevention strategies that aim to reduce the incidence of NMSCs. It will provide an overview of the mechanisms through which proanthocyanidins prevent mutations and skin carcinogenesis associated with UV radiation exposure.
Genotypic factors play a crucial role in the pathogenesis of NMSC. According to Pellegrini et al. (2485), all forms of cancer are associated with genetic mutations that confer the cells some characteristics such as angiogenesis, metastases, evasion of apoptosis, loss of growth inhibition factors and unlimited proliferation capacity. Development of any form of cancer is associated with two genes: tumor suppressor genes and oncogenes. Tumor suppressor genes prevent the proliferation of cells with errors by inhibiting the cell cycle. These genes regulate cell growth signals negatively to allow DNA repair. They prevent cancer by controlling cell growth and triggering apoptosis to prevent the spread of mutated cells. Proto-oncogenes are cell growth signals that contribute to cancer by causing uncontrolled cell growth. Mutations of oncogenes amplify cell growth signals and inhibit control of cell growth by the cell homeostasis. Unlike other genetic disorders, cancer occurs after the accumulation of genetic alterations.
The genetic alterations underlying the development of NMSCs are well-established. Griewank et al. (80356) note that mutations of the telomerase (TERT) promoter gene is the most common genetic event associated with the pathogenesis of NMSCs. According to Vinagre et al. (124), a TRAP assay has revealed telomerase activity in NMSCs in both tumor and non-tumor free areas. A telomere is DNA sequences that protect the termini of the chromosomes. The role of TERT is to shorten telomeres after each cell division by inhibiting telomerase activity. Telomeres become dysfunctional when they shorten to a critical size and enter senescence (a permanent growth arrest stage). The length of telomere plays a crucial role in the development of NMSCs. NMSC is characterized by increased telomerase expression that maintains telomere length thereby allowing division of cancerous cells. TERT avoid senescence by increasing the expression of telomerase to preserve the length of the telomere enabling infinite proliferation stimulated by oncogenes. Expression of TERT and telomerase activity is the hallmark of NMSCs.
Research suggests that Tert mutations are prevalent in BCC and SCC. A study by Griewank et al. (80357) found that 50% of SCC and 56% of BCC are characterized by mutation of the Tert promoter genes. The high frequency of Tert mutations in BCC and SCC suggests that increase telomerase expression play a critical role in the pathogenesis of BCC and SCC. BCC shows alterations that lead to the mutation of patched 1 (PTCH-1) and p53 genes which play a crucial role in tumor suppression. The mutation of PTCH-1 gene shows the importance of the hedgehog signaling pathway in the pathogenesis of BCC. The loss of PTCH-1 activity allows the uncontrolled proliferation of damaged genetic material. According to Pellegrini et al. (2487) loss of PTCH-I function due to inactivating mutations is associated with 90% of BCCs. P53 protects an individual from NMSCs by arresting cell cycle for DNA repair or apoptosis to occur and inhibit replication of mutated genes.
On the contrary, SCC is characterized by genetic alterations leading to activation of AKT and MAPK signaling pathway such as mutations or overexpression of oncogenes such as EGFR and RAS. UVB induces a substitution of pyrimidine base in the DNA of mutated keratinocytes from CC to TT or C to T which is indicative of UV-induced changes rendering the tumor suppressor mechanism ineffective which in turn leads to an unchecked proliferation of mutated cells (Griewank et al., 80358). According to Pellegrini et al. (2488), mutated keratinocytes re-express FasL which allow the rapidly proliferating altered cells to evade the immune system. Fasl is a gene that governs the apoptosis resistance, and it is involved in immune evasion thus it can serve as a prime target in the prevention of NMSCs. The use of gene-specific short interfering RNAs has proven to be successful in silencing FasL and preventing tumor formation.
Telomerase expression in NMSCs plays a crucial role in maintaining chromosomal stability and telomere length that allows unregulated cell division while maintaining genetic stability by eliminating the senescence barrier. Another study by Populo et al. (2253) found 39% of cases of BCC are characterized by mutations of Tert promoter gene. Mutation of the Tert promote gene are significantly more frequent in individuals with high exposure to UV radiation and areas exposed to the sun as compared to sun-protected area. Similarly, Vinagre et al. (124) demonstrated that mutations in TERT promoter are common in NMSCs accounting for more than 50% of cases of SCC and 39 to 74% causes of BCC. These findings indicate that mutations increase TERT expression which allows the proliferation of tumor cells while avoiding senescence.
Tumor necrosis factor-alpha (TNFα) is associated with the development of SCC resulting from exposure to UV radiation. TNFα is a pro-inflammatory cytokine involved in several cellular functions including programmed cell death, cell proliferation, and survival. TNFα has anticancer properties because it signals tumor cells to die. However, TNFα promotes tumor by stimulating survi...