Genetics of Skin Cancer (PDQ®)–Health Professional Version
Executive Summary
This executive summary reviews the topics covered in this PDQ summary on the genetics of skin cancer, with hyperlinks to detailed sections below that describe the evidence on each topic.
- Inheritance and RiskMore than 100 types of tumors are clinically apparent on the skin; many are known to have familial and/or inherited components, either in isolation or as part of a syndrome with other features. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which are known collectively as nonmelanoma skin cancer, are two of the most common malignancies in the United States and are often caused by sun exposure, although several hereditary syndromes and genes are also associated with an increased risk of developing these cancers. Melanoma is less common than nonmelanoma skin cancer, but 5% to 10% of all melanomas arise in multiple-case families and may be inherited in an autosomal dominant fashion.
- Associated Genes and SyndromesSeveral genes and hereditary syndromes are associated with the development of skin cancer. Basal cell nevus syndrome (BCNS, caused by pathogenic variants in PTCH1 and PTCH2) is associated with an increased risk of BCC, while syndromes such as xeroderma pigmentosum (XP), oculocutaneous albinism, epidermolysis bullosa, and Fanconi anemia are associated with an increased risk of SCC. The major tumor suppressor gene associated with melanoma is CDKN2A; pathogenic variants in CDKN2A have been estimated to account for 35% to 40% of all familial melanomas. Pathogenic variants in many other genes, including CDK4, CDK6, BAP1, and BRCA2, have also been found to be associated with melanoma.Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including melanoma, but the clinical utility of these findings remains uncertain.
- Clinical ManagementRisk-reducing strategies for individuals with an increased hereditary predisposition to skin cancer are similar to recommendations for the general population, and include sun avoidance, use of sunscreen, use of sun-protective clothing, and avoidance of tanning beds. Chemopreventive agents such as isotretinoin and acitretin have been studied for the treatment of BCCs in patients with BCNS and XP and are associated with a significant decrease in the number of tumors per year. Vismodegib has also shown promise in reducing the per-patient annual rate of new BCCs requiring surgery among patients with BCNS. Isotretinoin has also been shown to reduce SCC incidence among patients with XP.Treatment of hereditary skin cancers is similar to the treatment of sporadic skin cancers. One study in an XP population found therapeutic use of fluorouracil (5-FU) to be efficacious, particularly in the treatment of extensive lesions. In addition to its role as a therapeutic and potential chemopreventive agent, vismodegib is also being studied for potential palliative effects for keratocystic odontogenic tumors in patients with BCNS.
- Psychosocial and Behavioral IssuesMost of the psychosocial literature about hereditary skin cancers has focused on patients with familial melanoma. In individuals at risk of familial melanoma, psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Interest in genetic testing for pathogenic variants in CDKN2A is generally high. Perceived benefits among individuals with a strong family history of melanoma include information about the risk of melanoma for themselves and their children and increased motivation for sun-protective behavior. A number of studies have examined risk-reducing and early-detection behaviors in individuals with a family history of melanoma. Overall, these studies indicate inconsistent adoption and maintenance of these behaviors. Intervention studies have targeted knowledge about melanoma, sun protection, and screening behaviors in family members of melanoma patients, with mixed results. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.
Introduction
[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. Refer to OMIM for more information.]
Structure of the Skin
The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocyte cancers.
Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartments—the avascular epidermis and the vascular dermis—with many cell types distributed in a connective tissue matrix, largely created by fibroblasts.[1]
The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. Basal keratinocytes lose contact with the basement membrane as they divide. As basal keratinocytes migrate toward the skin surface, they progressively differentiate to form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum.
The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer.[3]
Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]
Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can undergo malignant transformation into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are another cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]
The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]
Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]
Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]
These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.
Function of the Skin
The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma (reddening of the skin) associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender T-cell responses consisting of increased levels of TH1, TH2, or TH17 cells.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]
Clinical Presentation of Skin Cancers
While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim or can appear somewhat eczematous (refer to Figure 2 and Figure 3). They often ulcerate (refer to Figure 2). SCCs frequently have a thick keratin top layer (refer to Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI's website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.
Basal cell carcinomas
Squamous cell carcinomas
Melanomas
References
- Vandergriff TW, Bergstresser PR: Anatomy and physiology. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 43-54.
- Schirren CG, Rütten A, Kaudewitz P, et al.: Trichoblastoma and basal cell carcinoma are neoplasms with follicular differentiation sharing the same profile of cytokeratin intermediate filaments. Am J Dermatopathol 19 (4): 341-50, 1997. [PUBMED Abstract]
- Soyer HP, Rigel DS, Wurm EM: Actinic keratosis, basal cell carcinoma and squamous cell carcinoma. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1773-93.
- Lapouge G, Youssef KK, Vokaer B, et al.: Identifying the cellular origin of squamous skin tumors. Proc Natl Acad Sci U S A 108 (18): 7431-6, 2011. [PUBMED Abstract]
- Koster MI, Loomis CA, Koss TK, et al.: Skin development and maintenance. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 55-64.
- Kamino H, Reddy VB, Pui J: Fibrous and fibrohistiocytic proliferations of the skin and tendons. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1961-77.
- McCalmont TH: Adnexal neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1829-50.
- Kaddu S, Kohler S: Muscle, adipose and cartilage neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. [Philadelphia, Pa]: Elsevier Saunders, 2012, pp 1979-92.
- Harrington LE, Mangan PR, Weaver CT: Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18 (3): 349-56, 2006. [PUBMED Abstract]
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