The Most Common Type of Cancer in the Us Is Skin Cancer

Skin cancer, the growth of abnormal skin cells, is the most common type of cancer in the U.S., with Americans having a one-in-five chance of developing it over the course of their lifetime (Larson, Wells, Oberleitner, & Frey, 2015). The skin is the body’s largest organ, making up roughly 16% of a human’s mass (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

It is separated into two layers, the epidermis – the outer layer that interacts with the environment – and the dermis – the layer underneath the epidermis that contains hair follicles, glands, and nerves (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). In the epidermis, keratinocytes join together to create a physical and chemical barrier from external factors and accumulate melanin pigments as they mature (Figure 1) (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

Epidermal melanin functions to block UV penetration into the skin, and is produced in melanocytes, the second most abundant cell in the epidermis, after keratinocytes (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Skin cancer is classified as either melanoma or non-melanoma, the most common of which are basal cell carcinoma and squamous cell carcinoma.

Melanoma skin cancer is a dark pigmented, usually malignant tumor derived from melanocytes, while non-melanoma skin cancer arises from keratinocytes and is caused primarily by exposure to ultraviolet B rays (Larson, Wells, Oberleitner, & Frey, 2015). Malignant melanoma is the deadliest form of skin cancer with an 11% mortality rate and accounts for roughly three quarters of all deaths related to skin cancer, despite causing less than 10% of skin malignancies (Liu & Sheikh, 2014).

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This treatment-resistant and metastasis-prone cancer mainly targets fair-skinned populations living in warm, sunny climates (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). If caught early, many melanomas can be managed by surgical excision, but the chances of long term survival decrease as the cancer has time to metastasize, or spread, even with recent progress in targeted therapy and immunotherapy (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Once melanoma metastasizes from its origin into other tissues, the response rate to treatment decreases to approximately 5-10% and the 10 year survival rate becomes 10% (Liu & Sheikh, 2014). Non melanoma cancers are much more common, with an estimated 2-3 million cases occurring worldwide every year (Narayanan, Saladi, & Fox, 2010).

Both squamous and basal cell carcinoma are curable with appropriate treatment, although basal cell carcinomas, which make up about 80% of non-melanoma cases, have a higher rate of recurrence (Larson, Wells, Oberleitner, & Frey, 2015). Some carcinomas can be removed by surgery, radiation therapy, chemotherapy, and immune response modifier drugs. Targeted therapy, which works by interfering with signaling pathways that the cancer cells need for growth, is also emerging as a popular treatment option (Larson, Wells, Oberleitner, & Frey, 2015). As the most common form of cancer in the United States, skin cancer should become part of all schools’ health curriculum. Due to the rising incidence rates and the immediate benefit of being aware of environmental and genetic risk factors, public knowledge regarding skin cancer is needed now more than ever.

Figure 1. Epidermal Structure The epidermis is a self-renewing tissue that contains keratinocytes in various stages of terminal differentiation. Keratinocytes are created in the basal layer and move through the epidermis outward, going through a series of differentiation and receiving melanin in the form of melanosomes. Each layer is identified by the form and differentiation state of the keratinocytes as indicated by the expression of cytokeratins and proteins (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

Epidemiologic data from Canada, Europe, and the U.S. indicate a continuous and dramatic increase in skin cancer incidence over the last few decades, emphasizing the need for increased education regarding this disease. The combined melanoma incidence is increasing by roughly 2.6% each year, and every year in the U.S., squamous cell carcinoma incidence rises 3-10% and basal cell carcinoma incidence rises 20-80% (Apalla, Lallas, Sotiriou, Lazaridou, & Ioannides, 2017). Not only is the number of skin cancer victims growing, but the thickness of tumors is increasing as well. According to results of the Surveillance Epidemiology and End Results program, T3/T4 tumors have become significantly thicker over time, suggesting that rising skin cancer incidence is not just the result of more screenings and biopsies (Apalla, Lallas, Sotiriou, Lazaridou, & Ioannides, 2017).

The Dutch National Institute for Public Health and the Environment estimates that the number of cancer cases will continue to increase through 2060, largely as the result of changes to the environment and UVR exposure (Apalla, Lallas, Sotiriou, Lazaridou, & Ioannides, 2017). One of these changes – the depletion of the ozone layer as caused by the release of pollutants into the atmosphere – has been a cause for concern since the mid 1980s. The ozone layer, which forms a thin shield around the earth’s stratospheric atmosphere, absorbs all UVC radiation, most UVB radiation, and very little UVA radiation (Narayanan, Saladi, & Fox, 2010). The effects of UVB radiation, an agent that is known to induce skin cancer in a dose dependent way, are enhanced when the ozone is unable to prevent biologically damaging UVB from reaching the earth’s surface (Fabbrocini et al., 2010).

A 1% decrease in ozone levels has been found to correspond with a 1-2% increase in the mortality caused by melanoma, and a 10% decrease of the ozone could eventually be sufficient enough to increase the incidence of basal and squamous cell carcinomas by 30% and 50%, respectively (Fabbrocini et al., 2010). Furthermore, the long term elevation of temperature by 2ºC as a result of climate change could increase the carcinogenic impact of solar UV by 10% (Fabbrocini et al., 2010). Rises in temperature could also influence people’s behaviors and the amount of time they spend outdoors, leading to greater UV exposure. Beyond environmental changes, skin cancer incidence is expected to continue to increase due to prolonged life expectancy.

The UN’s Population Division of the Department of Economic and Social Affairs estimates that by 2050, 32% of the world population will be above the age of 60 (Apalla, Lallas, Sotiriou, Lazaridou, & Ioannides, 2017). Since keratinocyte cancers are most common in the elderly (the average age at the time of diagnosis is about 60), melanoma rates will likely follow this increase in age (Apalla, Lallas, Sotiriou, Lazaridou, & Ioannides, 2017). Despite not being a new disease, skin cancer is still an extremely pervasive disease and its incidence is only expected to go up in the future. In order to reverse these trends, schools worldwide should make skin cancer part of health curriculums.

In addition to becoming increasingly widespread, skin cancer is also a disease that has clear causes, the most prominent of which being UV radiation. Education provided by schools could be incredibly beneficial in preventing skin cancer by promoting safe behaviors when it comes to time in the sun. The development of the three most common types of skin cancer – basal cell carcinoma, squamous cell carcinoma, and malignant melanoma – are all molecularly and epidemiologically linked to UV radiation (UVR) exposure, which is identified as a complete carcinogen, capable of initiating and promoting tumors (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). UVR causes significant DNA damage and genetic mutations and is responsible for roughly 65% of cases of melanoma skin cancer and 90% of cases of non-melanoma skin cancer (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

UV photons wavelengths are between those of visible light and gamma radiation and can be divided into UV-A (315-400 nm), UV-B (280-315 nm), and UV-C (100-280 nm) (Narayanan, Saladi, & Fox, 2010). UV photons with shorter wavelengths (UV-B and UV-C) directly affect nucleotide base pairing in DNA, with pyrimidine bases being especially vulnerable to chemical alteration (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). This radiation severs internal 5-6 double bonds of pyrimidines, causing photolesions, and when this occurs between adjacent pyrimidines, abnormal covalent bonds form, altering the structure of DNA’s double helix (Figure 2) (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

One day’s worth of sun exposure causes approximately 105 photolesions in every skin cell, with each lesion impairing transcription, blocking DNA replication, and causing base pair abnormalities (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Photolesions also cause mutations known as “UV signature mutations” (such as TT→CC), an abundance of which can be found in cancer-regulatory genes, such as the p53 tumor suppressor gene (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). When p53 genes, which are responsible for DNA repair and the apoptosis of cells with lots of DNA damage, are mutated, they are no longer able to aid in the DNA repair process, which allows the spread of mutated keratinocytes and the development of skin cancer (Narayanan, Saladi, & Fox, 2010). UVR also causes mutations by generating reactive oxygen species (ROS) such as superoxide anion, the hydroxyl radical, and hydrogen peroxide (Figure 3) (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

Nucleotides are highly susceptible to free radical injury, and the oxidation of nucleotide bases causes mispairing, leading to mutations that can be carcinogenic (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). For instance, the transversion from guanine to thymine is a common mutation that occurs when ROS oxidizes guanine (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). The mutations caused by UVR reveal the importance of promoting sun safety in classrooms, especially considering western society’s tan seeking behaviors and the depletion of the ozone, which contribute to increased UV exposure. In the modern era, an additional concern regarding UVR comes from the growth of the indoor tanning salon industry. In the late 1980s, only 1% of Americans had ever used a tanning bed, while today, over 25% have (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

UV output from tanning beds can be up to ten times more powerful than sunlight, making them highly carcinogenic instruments that are impossible to use safely (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Due to the extreme UV radiation individuals are exposed to in tanning beds, lifetime risk of developing melanoma increases by 75% if people engage in artificial tanning before the age of 35 (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Decreasing UV radiation exposure, both naturally from sunlight and artificially from tanning bed use, may be the most effective way to reduce skin cancer incidence, and can only be achieved if children are taught to take precautions.

By being informed of the risks of UV radiation, people will learn to minimize sun exposure during peak hours (10 am – 4 pm), wear sun protective clothing, use sunscreen with both UVA/UVB blocks, and avoid tanning beds and laps (Narayanan, Saladi, & Fox, 2010). Taking these steps early in life will reduce individuals’ cumulative lifelong sun exposure and along with it their risk for developing skin cancer. Simple changes in behavior and lifestyle can prevent repeated sun damage and the eventual development of skin cancer, but it is up to schools whether their students will receive this invaluable knowledge before it is too late.

While recognizing the relationship between the sun and skin cancer will help people avoid carcinogenic radiation, understanding the genetic factors associated with skin cancer will allow students to identify whether they are predisposed to develop the disease. Education can’t help people evade genetic causes of skin cancer, but it will encourage them to be vigilant of skin cancer symptoms if their heredity suggests they could be at greater risk. A major factor involved in the development of skin cancer is having a fair complexion, as caused by low levels of eumelanin in the epidermis (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

Epidermal melanin, which is made up of subunits of pigment species created by oxidation and cyclization of the amino acid tyrosine, exists in two forms – eumelanin, a dark pigment expressed in the skin of highly pigmented individuals, and pheomelanin, a light pigment caused by the incorporation of cysteines into early melanin (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Eumelanin is much more efficient at blocking UV photons than pheomelanin, which explains why fair skinned individuals, who lack much epidermal eumelanin, are more UV sensitive and have a higher risk of developing skin cancer than dark skinned individuals. Due to the proto protection offered by epidermal melanin, which provides a sun protection factor (SPF) of up to 13.4 in blacks, black epidermis transmits 7.4% of UVB and 17.5% of UVA, compared with 24% and 55% in Caucasian epidermis, respectively (Narayanan, Saladi, & Fox, 2010).

The “Fitzpatrick Scale” illustrates the six phototypes that describe skin color using basal complexion, melanin level, inflammatory response to UV, and cancer risk (Figure 4) (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). A low Fitzpatrick phototype correlates with both a minimal erythematous dose (the amount of UV needed to induce sunburn in the skin) and a high skin cancer risk (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Genetic risks also come from having low penetrance susceptibility genes, such as the melanocortin-1 receptor (MC1R), which can be related to skin pigmentation and present another cause for one to be predisposed to developing skin cancer (Gerstenblith, Landi, & Shi, 2010).

The melanocortin 1 receptor (MC1R), which is typically associated with features including red hair, pale skin, and freckles, is located on the surface of melanocytes where it bonds to an α-melanocyte stimulating hormone (MSH) and transmits signals into the cell through the activation of adenylyl cyclase and the generation of cAMP (Figure 5) (Gerstenblith, Landi, & Shi, 2010). cAMP signaling activates the protein kinase A cascade which then leads to increased levels of enzymes to enhance melanocytes’ production and export of melanin (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). The increased production and accumulation of melanin – specifically eumelanin – in the epidermis, as caused by MC1R’s role in inducing pigment synthesis, works to block the penetration of UV into the skin, decreasing mutagenesis and skin cancer risk (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). MC1R signals also decrease mutations caused by UV radiation by enhancing melanocyte genome maintenance pathways and promoting excision DNA repair and oxidative resistance (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).

The loss of signaling MC1R alleles (such as RHC – red hair color) is associated with a four times increase in the lifetime risk of skin cancers (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). A family history of melanoma might also put an individual at a greater risk. 8-12% of melanoma cases involve a patient with family members who had skin cancer, and individuals with affected relatives are more likely to develop melanoma at an earlier age and develop multiple melanoma lesions (Liu & Sheikh, 2014). Familial melanoma development has been associated with the oncogene cyclin-dependent kinase 4 (CDK4) and the tumor suppressor gene (CDKN2A), which encodes p16IKN4a (Liu & Sheikh, 2014).

This predisposition is inherited through autosomal dominant inheritance, with a 53% penetrance rate by the 8th decade (Liu & Sheikh, 2014). Upon activation by Cyclin D1, CDK4 acts as a proto-oncogene that advances cell progression from G1 to S phase, promoting cell proliferation, while p16INK4a inhibits CDK4 action, halting cell division (Liu & Sheikh, 2014). CDKN2A alterations account for roughly 20-40% of melanomas occurring in families with three or more affected individuals (Gerstenblith, Landi, & Shi, 2010). By being aware of genetic factors that might make one more likely to develop skin cancer, individuals will have a better understanding of whether they are inherently at greater risk and take extra precautions if they are. Students will also be more likely to achieve an early diagnosis through skin self examination or physicians’ surveillance if they know they are part of a high risk population, which is vital to reducing the risk of metastasis and increasing the chances of survival. Schools should take the opportunity to provide information regarding genetic risks so that high risk students will go out of their way to protect their skin and be more prepared and well informed if they are eventually diagnosed.

Figure 4. Pigmentation and Skin Cancer Risk Fair-skinned individuals with low levels of melanin in the epidermis display a UV sensitive phenotype and are likely to burn following UVR exposure. Mutations that contribute to fair complexion and tanning impairment – such as defects in the MC1R – may also be associated with weak UV resistance (D’Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013).