Genetics of Skin Cancer (PDQ®)

Structure of the Skin

The genetics of skin cancer is an extremely broad topic. More than 100 types of tumors are clinically apparent on the skin; many of them 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]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

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, along with interspersed melanocytes. 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's surface, they progressively differentiate, lose their nuclei, and form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum, which serves as a protective covering of the body.

The true cytologic origin of BCC is unclear. BCC and basal cell keratinocytes share many histological 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 traveling along nerves.[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 the lung and the uterine cervix, can give rise to SCCs. This cancer has somewhat differing behavior depending on its tissue source. Even in cancer derived from the skin, SCC from different anatomic locations can have differing levels of aggressiveness; for example, SCC from glabrous (smooth, hairless) sun-exposed 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. Melanocytes contain melanin, which is packaged into melanosomes and transported to nearby keratinocytes to induce pigmentation of the skin. Melanin provides a barrier for the nuclei of keratinocytes against ultraviolet radiation and also plays a role in the immune system.[5]

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 period of time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[6]

The dermis is largely composed of an extracellular matrix. Prominent cell types and organelles in this compartment are fibroblasts, endothelial cells, smooth muscle cells, transient immune system cells, blood vessels, and nerves. When malignant transformation occurs, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, or 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.[7]

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.[8]

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.[9]

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 (extensive reddening of the skin) associated with severe sunburn, 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 helper T cells (T_H)1, T_H2, or T_H17.[10] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Even small breaks in the skin can potentially lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system and has a role in the prevention of infection. It may also be important in immune surveillance against cancer. Immunosuppression, such as when it is induced intentionally after solid-organ transplantation to reduce the risk of transplanted organ rejection, 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 (for more information, see Figure 2 and Figure 3). They often ulcerate (for more information, see Figure 2). SCCs frequently have a thick keratin top layer (for more information, see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by dark pigment with asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). For more information about ABCDE criteria, see What Does Melanoma Look Like? on NCI's website. Photographs representing typical clinical presentations of these cancers are shown below.

Basal cell carcinomas

Figure 2. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

Figure 3. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Squamous cell carcinomas

Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Melanomas

Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

References

1. Vandergriff TW, Bergstresser PR: Anatomy and physiology. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 43-54.
2. 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: 9261468]
3. 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. Elsevier Saunders, 2012, pp 1773-93.
4. 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. [PMC free article: PMC3088632] [PubMed: 21502497]
5. Lin JY, Fisher DE: Melanocyte biology and skin pigmentation. Nature 445 (7130): 843-50, 2007. [PubMed: 17314970]
6. Koster MI, Loomis CA, Koss TK, et al.: Skin development and maintenance. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 55-64.
7. 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. Elsevier Saunders, 2012, pp 1961-77.
8. McCalmont TH: Adnexal neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 1829-50.
9. Kaddu S, Kohler S: Muscle, adipose and cartilage neoplasms. In: Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology. 3rd ed. Elsevier Saunders, 2012, pp 1979-92.
10. 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: 16616472]

Introduction

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. With early detection, the prognosis for BCC is excellent.

Risk Factors for Basal Cell Carcinoma

This section focuses on risk factors in individuals at increased hereditary risk of developing BCC. For more information about risk factors for BCC in the general population, see Skin Cancer Prevention.

Major Genes for Basal Cell Carcinoma

Putative Genes for Basal Cell Carcinoma

Syndromes Associated With a Predisposition to Basal Cell Carcinoma

Basal cell nevus syndrome

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid BCC syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[41] The syndrome is notable for complete penetrance and high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[30,42] The clinical features of BCNS differ more among families than within families.[43] BCNS is primarily associated with germline pathogenic variants in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[44-46]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline pathogenic variants of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS pathogenic variant has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[41] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing loss of heterozygosity (LOH) for PTCH1.[47] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 pathogenic variant as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[48-52] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[53]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (for more information, see Table 1).[54-57] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying carriers of pathogenic variants. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[57] PTCH1 pathogenic variants are found in 60% to 85% of patients who meet clinical criteria.[58,59] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[51,55,60] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[61] Ameloblastomas, aggressive tumors of the odontogenic epithelium in the jaw, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[62]

Other associated benign neoplasms include gastric hamartomatous polyps,[63] congenital pulmonary cysts,[64] cardiac fibromas,[65] meningiomas,[66-68] craniopharyngiomas,[69] fetal rhabdomyomas,[70] leiomyomas,[71] mesenchymomas,[72] basaloid follicular hamartomas,[73] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[74-76] In addition, radiation therapy of malignant medulloblastomas in the BCNS population may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[50,51,71]

The diagnostic criteria for BCNS are described in Table 1 below.

Table

Table 1. Comparison of Diagnostic Criteria for Basal Cell Nevus Syndrome (BCNS).

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon-like lesions, while larger lesions demonstrate more classic cutaneous features.[77] Nonpigmented BCCs are more common than pigmented lesions.[78] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[55,60] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[78] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[41] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[55,79,80] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[80] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[55,71] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.

Variants in other genes associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% CI, 20–34), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 30–40) (HR, 1.64; 95% CI, 1.04–2.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 28–37) relative to a median onset of 41 years (95% CI, 32–48) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.08–1.93, P = .014).[81]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[51,55,60,82] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[83,84] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[85] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[51,66] Other reported malignancies include ovarian carcinoma,[86] ovarian fibrosarcoma,[87,88] astrocytoma,[89] melanoma,[90] Hodgkin disease,[91,92] rhabdomyosarcoma,[93] and undifferentiated sinonasal carcinoma.[94]

Odontogenic keratocysts–or keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working group–are one of the major features of BCNS.[95] Demonstration of clonal LOH of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[47] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[53,96] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[95,97] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[95] A study that analyzed the rate of PTCH1 pathogenic variants in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 pathogenic variant and an additional 3 individuals had somatic mutations in this gene.[98] Individuals with germline PTCH1 pathogenic variants had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[55,99] with higher rates of occurrence in young females.[100]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[60] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[101]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri in the brain;[102,103] fused, splayed or bifid ribs;[104] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria by diagnostic x-ray imaging.[59] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Table

Table 2. Frequency of Nonmalignant Findings in Basal Cell Nevus Syndrome (BCNS).

Individuals with PTCH2 pathogenic variants may have a milder phenotype of BCNS than those with PTCH1 variants. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[105]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[106] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline pathogenic variants in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[45,46,107] These pathogenic variants were first identified in individuals with childhood medulloblastoma,[108] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU pathogenic variants than in those with PTCH1 variants.[45] SUFU pathogenic variants may also be associated with an increased predisposition to meningioma.[68,107,109] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU pathogenic variants for individuals with BCNS who do not have an identifiable PTCH1 variant.

Rare syndromes

Rombo syndrome

Rombo syndrome is a very rare genodermatosis or genetic disorder associated with BCC. It is thought to have an autosomal dominant inheritance pattern, and it has been outlined in three case series in the literature.[111-113] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[111] Development of BCC occurs in the fourth decade.[111] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[111,113] Missing, irregularly distributed, and/or misdirected eyelashes and eyebrows are another associated finding.[111,112] The genetic basis of Rombo syndrome is not known.

Bazex-Dupré-Christol syndrome

Bazex-Dupré-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[114-116] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[117] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[118]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[114] Documented hair changes with Bazex-Dupré-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[119] a twisted/flattened appearance of the hair shaft on electron microscopy,[120] and increased hair shaft diameter on polarizing light microscopy.[116] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[116] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[121,122]

Epidermolysis bullosa simplex

A rare, severe subtype of epidermolysis bullosa simplex (EBS), previously known as Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with pathogenic variants in either keratin-5 (KRT5) or keratin-14 (KRT14).[123,124] This severe subtype of EBS occasionally results in mortality in early childhood.[125] It has an estimated prevalence of 0.02 per million individuals in the United States and an incidence of 1.16 per million live births.[126] One report cites an incidence of BCC of 44% by age 55 years in this population.[127] Individuals who inherit two EBS pathogenic variants may present with a more severe phenotype.[128] Other less phenotypically severe subtypes of EBS can also be caused by pathogenic variants in either KRT5 or KRT14.[123] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 pathogenic variants.[129]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

Table

Table 3. Basal Cell Carcinoma (BCC) Syndromes.

For more information, see the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section.

Interventions

Screening

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once a BCC is detected on the skin of an individual, the National Comprehensive Cancer Network recommends that he/she have a complete skin examination biannually or annually for the first 5 years after the BCC is detected. After 5 years, skin examinations are recommended at least once a year for life.[138]

Table 4 summarizes available clinical practice guidelines for the surveillance of individuals with BCNS.

Table

Table 4. Available Recommendations for Surveillance in BCNS.

Level of evidence: 5

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Introduction

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of keratinocyte carcinomas (basal cell carcinoma [BCC] and SCC), annual incidence estimates range from 1 million to 5.4 million cases in the United States.[1-3] Multiple studies indicate an increased risk of SCC after a first keratinocyte carcinoma; a meta-analysis and review of 45 studies estimated that after a primary SCC diagnosis, 13.3% of individuals would develop a second SCC (95% confidence interval [CI], 7.4%–22.8%).[4]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Risk Factors for Squamous Cell Carcinoma

Syndromes and Genes Associated With a Predisposition for Squamous Cell Carcinoma

Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important pathogenic variants of the gene as causal. The disorders resulting from single-gene pathogenic variants within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine because of the rarity of the genetic variant.

Identification of a strong environmental risk factor—chronic exposure to UV radiation—makes it difficult to apply genetic causation for SCC of the skin. Although the risk of UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of cases of SCC of the skin is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin owing to: (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy, and (2) the relatively low potential for metastasis. Moreover, NMSC is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.

With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.

Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 5 below.

Table

Table 5. Hereditary Syndromes Associated with Squamous Cell Carcinoma of the Skin.

Oculocutaneous albinism

Albinism is a major risk factor for skin cancer in individuals of African ancestry.[20,78] One report describing a cohort of 350 albinos in Tanzania found 104 cutaneous cancers; of these, 100 were SCCs, three were BCCs, and one was melanoma.[79] The median age for this population was 10 years. Similar proportions of skin cancer diagnoses were observed in a Nigerian population, with 62% of dermatological malignancies diagnosed as SCC, 16% as melanoma, and 8% as BCC.[20] Of note, some melanomas found in individuals with albinism do contain melanin.[80]

SCC occurring at extremely early ages is a hallmark of oculocutaneous albinism. In a cohort of nearly 1,000 Nigerian patients with albinism, all had malignant or premalignant cutaneous lesions by age 20 years.[81]

Two types of oculocutaneous albinism are known to be associated with increased risk of SCC of the skin. Oculocutaneous albinism type 1, or tyrosinase-related albinism, is caused by pathogenic variants in the tyrosinase gene, TYR, located on the long arm of chromosome 11. This type of albinism accounts for about one-half of cases in individuals of Caucasian ancestry.[82] The OCA2 gene, also known as the P gene, is altered in oculocutaneous albinism type 2, or tyrosinase-positive albinism. Both disorders are autosomal recessive, with frequent compound heterozygosity.

Tyrosinase acts as the critical enzyme in the synthesis of melanin in melanocytes. A variant in this gene in oculocutaneous albinism type 1 produces proteins with minimal to no activity, corresponding to the OCA1B and OCA1A phenotypes, respectively. Individuals with OCA1B have light skin, hair, and eye coloring at birth but develop some pigment during their lifetimes, while the coloring of those with OCA1A does not darken with age.

The gene product of OCA2 is a protein found in the membrane of melanosomes. Its function is unknown, but it may play a role in maintaining the structure or pH of this environment.[83] Murine models with variants in this gene had significantly decreased melanin production compared with normal controls.[84] In one international study of individuals with albinism, biallelic variants in OCA2 were found in 17% of participants.[85]

Genetic variants in SLC45A2 (MATP associated with OCA4), SLC24A5 (associated with OCA6), and TYRP1 (tyrosinase-related protein 1 associated with OCA3) are associated with less common types of oculocutaneous albinism. Reported incidences for these genes in an international population of patients with albinism are 7% for SLC45A2, 1% for TYRP1, and less than 0.5% for SLC24A5.[85] SLC45A2 is found in 24% of oculocutaneous albinism cases in Japan, making it the most common type of albinism among Japanese individuals with identifiable variants.[86] A study of 22 individuals of Italian ancestry without pathogenic variants in TYR, OCA2, or TYRP1 found 5 individuals with biallelic variants in SLC45A2, 4 of whom met clinical criteria for a diagnosis of oculocutaneous albinism.[87] Collectively, more than 600 unique ocular albinism–related genetic variants have been identified.[88] The increased risk of SCC of the skin in people with these variants has not been quantified. It is generally assumed to be similar to other types of albinism. Of note, a meta-analysis demonstrated that the SLC45A2 p.Phe374Leu variant was protective for melanoma, with an OR of 0.41 (95% CI, 0.33–0.50; P = 3.50 x 10^-17).[89] However, at this time, it should be noted that clinical testing is not routinely performed for protective variants.

Additional genes associated with oculocutaneous albinism have been found in small numbers of patients. OCA5, located on chromosome 4q24, has been identified in a Pakistani family, whereas OCA6 appears to be caused by pathogenic variants in SLC24A5 on chromosome 15q21.[90-92] Pathogenic variants in C10orf11 (LRMDA) cause OCA7, which has been found in patients from the Faroe Islands and Denmark.[93] Small numbers of pathogenic variant carriers have been reported to date. One woman with OCA6 had actinic keratosis, but the incidence of skin cancers in these populations is unknown.

Although oculocutaneous albinism is inherited as an autosomal recessive disorder in most instances, one study has found that heterozygous variants in genes such as TYR, OCA2, TYRP1, and SLC45A2 are overrepresented in families with multiple cases of melanoma. Further investigation is warranted to determine if these genes may be moderate penetrance melanoma susceptibility genes in heterozygotes.[94]

Table

Table 6. Types of Oculocutaneous Albinism (OCA).

Fanconi anemia

Fanconi anemia is a complex disorder that is characterized by increased incidence of hematologic and solid tumors, including SCC of the skin. Fanconi anemia is inherited as an autosomal recessive disease. It is a relatively rare syndrome with an estimated carrier frequency of one in 181 individuals in the United States (range: 1 in 156 to 1 in 209) and a carrier frequency of up to 1 in 100 individuals of Ashkenazi Jewish ancestry.[165] Leukemia is the most commonly reported cancer in this population, but increased rates of gastrointestinal, head and neck, and gynecologic cancers have also been seen.[166] By age 40 years, individuals affected with Fanconi anemia have an 8% risk per year of developing a solid tumor;[166] the median age of diagnosis for solid tumors is 26 years.[167] Multiple cases of cancers of the brain, breast, lung, and kidney (Wilms tumor) have been reported in this population.[167] Data on the incidence of NMSCs in this population are sparse; however, review of the literature suggests that the age of diagnosis is between the mid-20s and early 30s and that women seem to be affected more often than men.[167-171]

Individuals with this disease have increased susceptibility to DNA cross-linking agents (e.g., mitomycin-C or diepoxybutane) and ionizing and UV radiation. The diagnosis of this disease is made by observing increased chromosomal breakage, rearrangements, or exchanges in cells after exposure to carcinogens such as diepoxybutane.

Seventeen complementation groups have been identified for Fanconi anemia; details regarding the genes associated with these groups are listed in Table 7 below.[172] Exome sequencing has revealed that a subset of individuals can carry multiple heterozygous pathogenic variants in Fanconi anemia genes,[173] which may impact phenotypic presentation.

Table

Table 7. Genes Associated with Fanconi Anemia (FA).

The proteins involved with DNA crosslink repairs are called the FANC pathway because of their involvement in Fanconi anemia.[174] They interact with several other proteins associated with hereditary cancer risk, including those in Bloom syndrome and ataxia-telangiectasia. Further investigation has revealed that FANCD1 is the same gene as BRCA2, a gene that causes predisposition to breast and ovarian cancer.[175] Other Fanconi anemia genes, FANCJ (BRIP1) and FANCN (PALB2), have also been identified as rare breast cancer susceptibility genes.[176] Individuals who are heterozygous carriers of other Fanconi anemia–associated variants do not appear to have an increased cancer risk, with the possible exception of a twofold increase in breast cancer incidence in carriers of FANCC pathogenic variants.[177]

In 2018, a group reported a significant increase in SCC cases (OR, 1.69; 95% CI, 1.26–2.26) associated with a specific BRCA2 allele, which is relatively prevalent in the Icelandic population (K3326X; allele frequency, 1.1%).[178] This allele results in normal production of an altered protein, and the authors hypothesized carriers have an increased sensitivity to environmental factors, which require DNA repair. This variant was also associated with an increased risk of small cell lung cancer, breast cancer, and ovarian cancer (but lower than the risk associated with the BRCA pathogenic variants that decrease protein levels).

MC1R

A meta-analysis showed that the more MC1R pathogenic variants an individual carried, the higher his/her risk was to develop SCC and BCC. Individuals with two or more MC1R pathogenic variants had a summary OR of 2.48 (95% CI, 1.96–3.15) for BCC and a summary OR of 2.80 (95% CI, 1.71–4.57) for SCC; these risks increased when individuals had red hair.[242] A study of individuals diagnosed with BCC before age 40 years also found a stronger association between BCC and MC1R pathogenic variants in those with phenotypic characteristics that are not traditionally considered high risk. For more information, see the section on MC1R in the Melanoma section.[243]

Interventions

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Introduction

Rare, high-penetrance and common, low-penetrance genetic factors for melanoma have been identified, and approximately 5% to 10% of all melanomas arise in multiple-case families. However, a significant fraction of these families do not have detectable pathogenic variants in specific susceptibility genes. The frequency with which multiple-case families are ascertained and specific genetic variants are identified differs substantially between populations and geographic regions. A major population-based study has concluded that the high-penetrance susceptibility gene CDKN2A does not make a large contribution to the incidence of melanoma.[1]

Melanoma can also occur in other parts of the body, such as the eye and brain. For more information about melanoma of the eye, see Intraocular (Uveal) Melanoma Treatment.

Risk Factors for Melanoma

This section focuses on risk factors in individuals at increased hereditary risk of developing melanoma. For more information about melanoma risk factors in the general population, see Skin Cancer Prevention.

Major Genes for Melanoma

Minor Genes (Genetic Modifiers) for Melanoma

Other Cancer Susceptibility Genes

Melanoma Risk Assessment

Patients with a personal history of melanoma or dysplastic nevi should be asked to provide information regarding a family history of melanoma and other cancers to detect the presence of familial melanoma. Age at diagnosis in family members and pathologic confirmation, if available, should also be sought. The presence of MPM in the same individual may also provide a clue to an underlying genetic susceptibility. Approximately 30% of affected individuals in hereditary melanoma kindreds have more than one primary melanoma, versus 4% of sporadic melanoma patients.[217] Family histories should be updated regularly; an annual review is often recommended.

For individuals without a personal history of melanoma, several models have been suggested for prediction of melanoma risk.[218] The models differ in performance with respect to sensitivity and specificity, including differences by sex in some models. Data from the Nurses' Health Study were used to create a model that included gender, age, family history of melanoma, number of severe sunburns, number of moles larger than 3 mm on the limbs, and hair color.[219] The concordance statistic for this model was 0.62 (95% CI, 0.58–0.65). Another measure of baseline melanoma risk was derived from a case-control study of individuals with and without melanoma in the Philadelphia and San Francisco areas.[220] This model focused on gender, history of blistering sunburn, color of the complexion, number and size of moles, presence of freckling, presence of solar damage to the skin, absence of a tan, age, and geographic area of the United States. Attributable risk with this model was 86% for men and 89% for women. This predictive tool, the Melanoma Risk Assessment Tool, is available online. However, this tool was developed using a cohort of primarily White individuals without a personal or family history of melanoma or NMSC. It is designed for use by health professionals, and patients are encouraged to discuss results with their physicians. Additional external validation is appropriate before this tool can be adopted for widespread clinical use. Professional organizations have published genetic counseling referral guidelines for individuals with a history of melanoma.[34] For more information, see the Family history section.

Interventions

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173. Pasquali E, García-Borrón JC, Fargnoli MC, et al.: MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project. Int J Cancer 136 (3): 618-31, 2015. [PMC free article: PMC4378685] [PubMed: 24917043]
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175. Davies JR, Randerson-Moor J, Kukalizch K, et al.: Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study. Pigment Cell Melanoma Res 25 (3): 384-94, 2012. [PMC free article: PMC3490389] [PubMed: 22325793]
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186. Demenais F, Mohamdi H, Chaudru V, et al.: Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst 102 (20): 1568-83, 2010. [PMC free article: PMC2957428] [PubMed: 20876876]
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188. Helsing P, Nymoen DA, Rootwelt H, et al.: MC1R, ASIP, TYR, and TYRP1 gene variants in a population-based series of multiple primary melanomas. Genes Chromosomes Cancer 51 (7): 654-61, 2012. [PubMed: 22447455]
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201. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999. [PubMed: 10433620]
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203. van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al.: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42 (9): 711-9, 2005. [PMC free article: PMC1736136] [PubMed: 16141007]
204. Kadouri L, Temper M, Grenader T, et al.: Absence of founder BRCA1 and BRCA2 mutations in cutaneous malignant melanoma patients of Ashkenazi origin. Fam Cancer 8 (1): 29-32, 2009. [PubMed: 18679827]
205. Gumaste PV, Penn LA, Cymerman RM, et al.: Skin cancer risk in BRCA1/2 mutation carriers. Br J Dermatol 172 (6): 1498-506, 2015. [PMC free article: PMC5785081] [PubMed: 25524463]
206. Johansson PA, Nathan V, Bourke LM, et al.: Evaluation of the contribution of germline variants in BRCA1 and BRCA2 to uveal and cutaneous melanoma. Melanoma Res 29 (5): 483-490, 2019. [PMC free article: PMC6716616] [PubMed: 31464824]
207. Bui AN, LeBoeuf NR, Nambudiri VE: Skin cancer risk in CHEK2 mutation carriers. J Eur Acad Dermatol Venereol 35 (2): 353-359, 2021. [PubMed: 32531112]
208. Weischer M, Heerfordt IM, Bojesen SE, et al.: CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis. J Invest Dermatol 132 (2): 299-303, 2012. [PubMed: 21956126]
209. Mester J, Eng C: When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C Semin Med Genet 163C (2): 114-21, 2013. [PubMed: 23613428]
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219. Cho E, Rosner BA, Feskanich D, et al.: Risk factors and individual probabilities of melanoma for whites. J Clin Oncol 23 (12): 2669-75, 2005. [PubMed: 15837981]
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223. Hansson J, Bergenmar M, Hofer PA, et al.: Monitoring of kindreds with hereditary predisposition for cutaneous melanoma and dysplastic nevus syndrome: results of a Swedish preventive program. J Clin Oncol 25 (19): 2819-24, 2007. [PubMed: 17602087]
224. Salerni G, Carrera C, Lovatto L, et al.: Benefits of total body photography and digital dermatoscopy ("two-step method of digital follow-up") in the early diagnosis of melanoma in patients at high risk for melanoma. J Am Acad Dermatol 67 (1): e17-27, 2012. [PMC free article: PMC3215791] [PubMed: 21683472]
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228. Rulyak SJ, Kimmey MB, Veenstra DL, et al.: Cost-effectiveness of pancreatic cancer screening in familial pancreatic cancer kindreds. Gastrointest Endosc 57 (1): 23-9, 2003. [PubMed: 12518126]

Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis

Brooke-Spiegler Syndrome (BSS), familial cylindromatosis, and multiple familial trichoepithelioma (MFT) are all autosomal dominant syndromes with overlapping clinical characteristics with allelic variance.[1] Features of BSS include multiple skin appendage tumors such as cylindromas (tumors arising in the hair follicle stem cells), trichoepitheliomas (tumors arising in the hair follicle), and spiradenomas (benign tumors arising in the sweat gland). MFT is characterized by nonmalignant skin tumors, primarily trichoepitheliomas, and familial cylindromatosis manifests predominantly as cutaneous cylindromas. Onset of tumors for these syndromes is typically in late childhood or early adolescence, suggesting a hormonal influence.[2] There is some evidence of greater severity in females than in males. UV radiation appears to be a major initiating factor for cylindromas. Typical tumor sites for cylindromas in familial cylindromatosis are the scalp (81% of carriers), the trunk (69% of carriers), and the pubic area (42% of carriers).[3] Other tumors that can be associated with these syndromes include parotid gland tumors, basal cell adenomas, and basal cell carcinomas. For more information about BSS, see Table 3, Basal Cell Carcinoma (BCC) Syndromes.

Because pathogenic variants in CYLD on16q12-q13 have been identified in individuals with each of these disorders, these syndromes are thought to represent different phenotypic manifestations of the same disease.[4] Penetrance of pathogenic variants in CYLD is reported to be 60% to 100%.[3,5] In one study, 85% of the BSS families, 100% of familial cylindromatosis families, and only 44% of MFT families were found to have pathogenic variants in CYLD.[6] A second locus for MFT maps to 9p21, but the gene for this locus remains unknown.[7]

Given the potential for progressive enlargement, the preferred approach for cylindromas is ablation while the tumors are small and easily managed. Electrosurgery or Mohs micrographic surgery may be used for therapy, although excision of large lesions may require skin grafting for closure.[8] Trichoepitheliomas and spiradenomas typically remain smaller in size; thus, after the diagnosis is confirmed by skin biopsy, unless there is impingement on critical structures, further intervention is not required. If therapy is deemed necessary and appropriate, either electrosurgery or ablative laser therapy is a valid option.[8] Radiotherapy is not recommended for treatment of any of these tumors because a potential for increased tumor induction.

Level of evidence: 4

Sebaceous Carcinoma

Cutaneous sebaceous neoplasms may be associated with Muir-Torre syndrome (MTS). Multiple types of sebaceous tumors including sebaceous adenomas, epitheliomas, carcinomas, and keratoacanthomas or BCCs with sebaceous differentiation have been described. A variant of Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome, the MTS phenotype involves the synchronous or metachronous development of at least one cutaneous sebaceous neoplasm and at least one visceral malignancy. The visceral malignancies may be of gastrointestinal (colorectal, stomach, small bowel, liver, and bile duct) and/or genitourinary (endometrial and bladder) origin and typically demonstrate a less aggressive phenotype than non-MTS equivalent tumors.[9,10] MTS, inherited in an autosomal dominant fashion with high penetrance and variable expressivity, is associated with pathogenic variants in the mismatch repair genes MLH1, MSH2, and less commonly, MSH6.[11-16] In a study of 36 sebaceous lesions that included sebaceous carcinomas, sebaceous adenomas, and sebaceomas, 38.9% of lesions were missing one or more mismatch repair proteins by immunohistochemistry (IHC).[17] Of the ten individuals with absent staining of one or more proteins, five had gene testing that confirmed a diagnosis of Lynch syndrome. This result suggests that routine screening of sebaceous lesions by IHC may be useful in identification of individuals with Lynch syndrome. One study of the incidence of skin cancer in Lynch syndrome suggests there is an increase in sebaceous carcinoma and squamous cell carcinoma in these patients.[18]

While the commonly noted sebaceous hyperplasia has not been associated with MTS, any sebaceous lesion with atypical or difficult to classify histologic features should prompt further exploration of the patient’s family and personal medical history. Consideration should be given to referring patients with sebaceous neoplasms to medical geneticists or gastroenterologists to evaluate further for Lynch syndrome. While the diagnosis of visceral malignancy precedes that of cutaneous sebaceous neoplasms in the majority of patients, 22% of patients develop cutaneous sebaceous neoplasms first, offering an opportunity for visceral malignancy screening.[19] Current diagnosis of MTS is based upon clinical criteria but may be supported by immunohistochemical staining for MSH2, MLH1, and MSH6 as a screening mechanism before molecular genetic analysis.[12,14-16,20] Genetic counseling and testing for the patient and family members, with appropriate visceral malignancy screening regimens, should be pursued.

Level of evidence: 3

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)

Although cutaneous smooth muscle tumors (leiomyomas) are not themselves a form of skin cancer, multiple cutaneous leiomyomas are associated with renal cell cancer (RCC) in an inherited syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). Cutaneous leiomyomas present as firm, pink or reddish-brown papules and nodules distributed over the trunk and extremities and, occasionally, on the face. These lesions occur at a mean age of 25 years (age range, 10–47 y) and tend to increase in size and number with age. Lesions are sensitive to light touch and/or cold temperature and are, less commonly, painful. Pain is correlated with severity of cutaneous involvement.[21] The presence of multiple cutaneous leiomyomas is associated with HLRCC until proven otherwise and should prompt a genetic workup; a solitary leiomyoma requires careful analysis of family history. For more information, see Hereditary Leiomyomatosis and Renal Cell Cancer.

References

1. Bowen S, Gill M, Lee DA, et al.: Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol 124 (5): 919-20, 2005. [PubMed: 15854031]
2. Burrows NP, Jones RR, Smith NP: The clinicopathological features of familial cylindromas and trichoepitheliomas (Brooke-Spiegler syndrome): a report of two families. Clin Exp Dermatol 17 (5): 332-6, 1992. [PubMed: 1333921]
3. Rajan N, Langtry JA, Ashworth A, et al.: Tumor mapping in 2 large multigenerational families with CYLD mutations: implications for disease management and tumor induction. Arch Dermatol 145 (11): 1277-84, 2009. [PMC free article: PMC2935681] [PubMed: 19917957]
4. Young AL, Kellermayer R, Szigeti R, et al.: CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet 70 (3): 246-9, 2006. [PubMed: 16922728]
5. Welch JP, Wells RS, Kerr CB: Ancell-Spiegler cylindromas (turban tumours) and Brooke-Fordyce Trichoepitheliomas: evidence for a single genetic entity. J Med Genet 5 (1): 29-35, 1968. [PMC free article: PMC1468611] [PubMed: 5653864]
6. Saggar S, Chernoff KA, Lodha S, et al.: CYLD mutations in familial skin appendage tumours. J Med Genet 45 (5): 298-302, 2008. [PubMed: 18234730]
7. Harada H, Hashimoto K, Ko MS: The gene for multiple familial trichoepithelioma maps to chromosome 9p21. J Invest Dermatol 107 (1): 41-3, 1996. [PubMed: 8752837]
8. Rajan N, Trainer AH, Burn J, et al.: Familial cylindromatosis and brooke-spiegler syndrome: a review of current therapeutic approaches and the surgical challenges posed by two affected families. Dermatol Surg 35 (5): 845-52, 2009. [PubMed: 19397670]
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13. Mathiak M, Rütten A, Mangold E, et al.: Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test. Am J Surg Pathol 26 (3): 338-43, 2002. [PubMed: 11859205]
14. Mangold E, Rahner N, Friedrichs N, et al.: MSH6 mutation in Muir-Torre syndrome: could this be a rare finding? Br J Dermatol 156 (1): 158-62, 2007. [PubMed: 17199584]
15. Arnold A, Payne S, Fisher S, et al.: An individual with Muir-Torre syndrome found to have a pathogenic MSH6 gene mutation. Fam Cancer 6 (3): 317-21, 2007. [PubMed: 17323113]
16. Murphy HR, Armstrong R, Cairns D, et al.: Muir-Torre Syndrome: expanding the genotype and phenotype--a further family with a MSH6 mutation. Fam Cancer 7 (3): 255-7, 2008. [PubMed: 18236172]
17. Plocharczyk EF, Frankel WL, Hampel H, et al.: Mismatch repair protein deficiency is common in sebaceous neoplasms and suggests the importance of screening for Lynch syndrome. Am J Dermatopathol 35 (2): 191-5, 2013. [PubMed: 22722469]
18. Adan F, Crijns MB, Zandstra WSE, et al.: Cumulative risk of skin tumours in patients with Lynch syndrome. Br J Dermatol 179 (2): 522-523, 2018. [PubMed: 29542113]
19. Akhtar S, Oza KK, Khan SA, et al.: Muir-Torre syndrome: case report of a patient with concurrent jejunal and ureteral cancer and a review of the literature. J Am Acad Dermatol 41 (5 Pt 1): 681-6, 1999. [PubMed: 10534628]
20. Entius MM, Keller JJ, Drillenburg P, et al.: Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome. Clin Cancer Res 6 (5): 1784-9, 2000. [PubMed: 10815898]
21. Toro JR, Nickerson ML, Wei MH, et al.: Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73 (1): 95-106, 2003. [PMC free article: PMC1180594] [PubMed: 12772087]

Introduction

This section reviews the literature examining risk reduction and early-detection behaviors in individuals with heightened risk of melanoma resulting from their family history of the disease and in individuals from hereditary families who have been tested for melanoma high-risk pathogenic variant status. The review also addresses risk perception and communication in individuals at heightened risk of melanoma.

Interest in and Uptake of Genetic Testing for Risk of Melanoma

Currently, clinical testing for CDKN2A is not recommended outside the research context because most individuals from multiple-case families will not be identified as having a pathogenic variant in this gene, and because recommendations for those testing positive do not differ for multiple-case family members who test negative, or do not pursue testing.[1,2] Despite these cautions, CDKN2A testing is commercially available, and thus demand for the test will likely increase.[3] Arguments for the availability of genetic testing include that the results of testing could provide psychological security and contribute to enhanced screening and prevention efforts for those testing positive for CDKN2A.[4] For more information about melanoma genetic testing, see the Melanoma Risk Assessment section.

Few studies have examined motivation and interest in genetic testing for melanoma risk. In summary, the findings include the following:

• High, but not universal interest in genetic testing.[5-7]
• Articulated benefits of testing among those at heightened risk.[5,6,8]
• A relative lack of examination of potential limitations of testing or reasons to forgo testing.[5-7]

In Australia, a qualitative study (N = 40) found that almost all participants with a strong family history of melanoma were interested in genetic testing.[6,9] Genetic testing was favored by the participants as a means to gain information about their children's susceptibility to melanoma, to increase their understanding of their own risk, to advance melanoma research, and to provide increased motivation for sun-protective behavior.

A Dutch study examined interest in CDKN2A testing (p16-Leiden pathogenic variant). Of 510 letters sent to members of 18 p16-Leiden-positive families recruited from the Pigmented Lesions Clinic at the Leiden University Medical Center in the Netherlands, 488 individuals responded by attending clinic for physical examination; an additional 15 family members also accompanied these individuals. Of these, 403 individuals were eligible for genetic counseling. A total of 184 family members followed through with counseling, and 141 of them opted for genetic testing. After the counseling session, 94 individuals returned a completed questionnaire. Older age predicted higher interest in genetic testing; reasons for having genetic testing included learning personal risk (57%) and learning the risk of one's child carrying the pathogenic variant (69%). Most participants (88%) felt that genetic testing would contribute to diagnostics within their family. However, some individuals (40%) reported that they had not expected to receive risk information concerning pancreatic cancer, and half of the participants (49%) reported increased worry about the possibility of developing pancreatic cancer.[7] Finally, in an Arizona qualitative study of 22 individuals with a strong family history of melanoma, none elected genetic testing even though it was provided as an option for them.[8]

In an Australian study of 121 individuals with a strong family history of melanoma, participants completed questionnaires before genetic counseling and testing.[9] Distress (melanoma-specific distress and general distress) levels were very low in this population. The most important predictors of distress included a personal history of melanoma, having concerns about the impact of melanoma on family, having a high information-seeking disposition (monitoring style), a perceived importance of sun exposure in causing melanoma, and not having children.

Risk Awareness and Risk Reduction in Individuals at Increased Familial Risk of Melanoma

A number of studies have been conducted examining risk reduction via adoption of sun protection (including the use of sunscreen and protective clothing and shade seeking behavior) in individuals with a family history of melanoma. Overall, these studies indicate inconsistent adoption and maintenance of these behaviors. Most of these studies have been conducted with clinic-based populations that might be more prone to risk reduction and screening behaviors than those with a similar risk profile in the general population.[11]

In terms of sun protection, in a Swedish population, 87 young adults with dysplastic nevi were surveyed, and 70% estimated their melanoma risk to be equal or lower than that of the Swedish population in general, and one third reported frequent sunbathing behavior.[12] Another study examined 229 first-degree relatives (FDRs) referred by melanoma patients attending clinic appointments; those who were older, female, and had greater confidence in their ability to practice sun-protection were most likely to do so, but the utilization of sun-protective behavior was inconsistent.[13] Another study in the United States examined sun-protective behavior in 100 FDRs of melanoma clinic patients and found that less than one-third of patients use sunscreen routinely when in the sun and that more regular usage was related to higher education levels, higher self-efficacy for sun protection, and higher perceived melanoma risk. Perceived severity of melanoma and response-efficacy were not related to adoption of sun-protective behaviors.[14]

A study that focused on 68 minor children (aged 17 years or younger) of melanoma survivors demonstrated that while overall rates of sun-protective behavior were high (near 80%), the rates of sunburn were also high (49%).[15] The authors concluded that multiple methods of sun-protective behavior are warranted in these individuals. However, in the teenage years, there were significant reductions in sun protection indicating an even greater need for intervention in this group.

Another study based in the United Kingdom examined sunburn rates in 170 individuals with a family history of melanoma compared with 140 controls matched to age, sex, and geographical location. Of those with a melanoma family history, 31% reported sunburn in the previous summer (compared with 41% of controls); melanoma families reported better sun-protection behaviors than controls overall. Across controls and those with a family history of melanoma, younger males were more likely to report recent sunburns; also, across controls and those with a family history of melanoma, those relatives with atypical mole syndrome and a belief in their ability to prevent melanoma showed better sun protection.[16]

One qualitative study of 20 FDRs of melanoma patients recruited from a high-risk clinic at the University of Arizona identified perceived unmet needs for physician communication of risk status, including greater consistency in communication, education for patients concerning the importance of family history to risk status, and needs and desire for more complex advice (e.g., reapplication of sunscreen and wearing clothing with ultraviolet protection factor).[17]

A prospective study examined interest in and 3-month behavioral and psychosocial outcomes associated with disclosure of melanoma high-risk pathogenic variant research results in 19 individuals (three CDKN2A carriers).[18] All of the variant carriers, but only four of the noncarriers, had a family history of melanoma. Carrier status did not affect risk perception, distress, or sun-protection behaviors.

Screening Behaviors in Individuals at Increased Familial Risk of Melanoma

A number of studies have examined early-detection behaviors in individuals at increased risk of melanoma. In a U.S. sample of 404 siblings drawn from a clinic population of melanoma patients, only 42% of individuals had ever seen a dermatologist; 62% had engaged in skin self-examination; 27% had received a physician skin examination; and only 54% routinely used sunscreen. Female gender was related to greater sunscreen use; those older than age 50 years were more likely to have received a physician skin examination. Having a dermatologist was strongly related to all three outcomes (skin self-examination, physician examination, and sunscreen use).[21] In a U.S. study of 229 FDRs referred by patients attending clinic, about half (55%) reported ever having a total cutaneous examination, and slightly more (71%) reported ever performing skin self-examination. Common predictors of skin examination (physician and self-examinations) included physician recommendation and low perceived barriers of screening.[13] Interestingly, 14% of the sample had not told their primary care doctor about their sibling’s melanoma diagnosis. One U.S. study showed that half (53%) of FDRs had never received a total cutaneous screening by a physician; only 27% had received a physician recommendation to have a screening. Early detection adherence was related to the following: higher education level, more melanoma risk factors, health care provider recommendation for screening, perceived risk of melanoma, and perceived severity of melanoma. Parents of melanoma patients were less likely to have pursued screening than siblings and children.[22] A U.S. study examined intentions to receive a physician skin examination and to perform skin self-examination among FDRs of individuals diagnosed with melanoma who had not recently engaged in skin surveillance. Predictors of intentions included both benefits and barriers to screening and family support for screening, but not knowledge of recommended screening frequency.[23]

A cross-sectional Australian study of 120 individuals from families with a known CDKN2A pathogenic variant found that in the past 12 months, 50% reported engaging in skin self-examinations at least four times, and 43% had undergone at least one clinical skin examination. In contrast, 15% had not performed a skin self-examination in the past 12 months, and 27% had never had a clinical skin examination. Correlates of skin cancer screening behaviors included having a history of melanoma, a physician’s recommendation, and stronger behavioral intentions. Additional correlates for skin self-examination included self-efficacy, perceived efficacy of melanoma treatment, and melanoma-specific distress. Perceived risk of developing melanoma was not significantly associated with skin cancer screening behaviors.[24]

Psychosocial Outcomes of Genetic Counseling and Genetic Testing

A few small studies have examined distress and behavioral factors associated with CDKN2A testing for melanoma. In a Swedish clinic for individuals at high risk of melanoma resulting from dysplastic nevus syndrome, 11 unaffected, untested individuals drawn from families in which a CDKN2A pathogenic variant has been identified were examined. Most (9 of 11) reported no worry about increased melanoma risk. In assessments after disclosure of results, there were no increasing trends towards depression, anxiety, or increased melanoma-risk perception by test results, and no systematic change in sun-related habits by test results.[25]

A prospective study examined interest in and 3-month behavioral and psychosocial outcomes associated with disclosure of melanoma high-risk pathogenic variant research results in 19 individuals (three CDKN2A carriers).[18] All of the pathogenic variant carriers, but only four of the noncarriers, had a family history of melanoma. Carrier status did not affect risk perception, distress, or sun-protection behaviors.

In a randomized controlled trial, 73 adults with a family history of melanoma were randomly assigned to receive either genetic counseling with genotyping results (CDKN2A and MC1R) or usual care. Overall, participants in the intervention group reported a significant increase in frequency of skin self-examinations, compared with a slight decrease among those in the control group. In addition, intervention participants reported a smaller decrease in frequency of wearing a shirt for sun protection compared with control participants. No other differences in sun protection habits were noted. These results should be interpreted with caution, as only five individuals (three in the intervention arm) had a pathogenic variant for one or both of the genes. Nonetheless, study results support the notion that genetic testing for melanoma does not lead to false reassurance and reduced sun protection behaviors among those who test negative.[26]

Another study examined behavioral factors associated with CDKN2A carrier status among 64 individuals from two large Utah families in which a CDKN2A pathogenic variant had been identified. The individuals received extensive recommendations for sun protection and screening. Questionnaires conducted one month after receipt of genetic test results and recommendations showed increased intention for skin examinations (self-examinations and health care professional examinations), regardless of whether individuals were found to be CDKN2A carriers or noncarriers. Rates of over screening (>1 skin self-examination per month) also increased in CDKN2A carriers.[27] In a follow-up study one month later with the same sample, CDKN2A carriers showed marginally increased intentions for sun-protective behaviors; CDKN2A noncarriers showed no increase in overall photoprotection but a shift to using sun-protective clothing rather than sun avoidance.[28] Thirty-seven individuals from the same cohort were assessed for psychosocial and behavioral outcomes 2 years posttesting. Levels of anxiety, depression, melanoma worry, and pancreatic cancer worry were all low and decreased over time, with more perceived benefits of testing noted than drawbacks of testing.[29] Adherence to annual total-body skin examinations significantly increased among unaffected carriers (from 40% at baseline to 70% at 2 years) but decreased among unaffected noncarriers (from 56% at baseline to 13% at 2 years). Affected carriers were adherent at both assessments (91% and 82%, respectively).[30]

References

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2. Kefford RF, Mann GJ: Is there a role for genetic testing in patients with melanoma? Curr Opin Oncol 15 (2): 157-61, 2003. [PubMed: 12601281]
3. Hansen CB, Wadge LM, Lowstuter K, et al.: Clinical germline genetic testing for melanoma. Lancet Oncol 5 (5): 314-9, 2004. [PubMed: 15120668]
4. Bergman W, Gruis NA: Phenotypic variation in familial melanoma: consequences for predictive DNA testing. Arch Dermatol 143 (4): 525-6, 2007. [PubMed: 17438187]
5. Bränström R, Kasparian NA, Affleck P, et al.: Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma. Eur J Cancer 48 (16): 3052-62, 2012. [PubMed: 22726816]
6. Kasparian NA, Meiser B, Butow PN, et al.: Anticipated uptake of genetic testing for familial melanoma in an Australian sample: An exploratory study. Psychooncology 16 (1): 69-78, 2007. [PubMed: 16874747]
7. de Snoo FA, Riedijk SR, van Mil AM, et al.: Genetic testing in familial melanoma: uptake and implications. Psychooncology 17 (8): 790-6, 2008. [PubMed: 18613292]
8. Loescher LJ, Crist JD, Siaki LA: Perceived intrafamily melanoma risk communication. Cancer Nurs 32 (3): 203-10, 2009 May-Jun. [PMC free article: PMC2909761] [PubMed: 19295423]
9. Kasparian NA, Butow PN, Meiser B, et al.: High- and average-risk individuals' beliefs about, and perceptions of, malignant melanoma: an Australian perspective. Psychooncology 17 (3): 270-9, 2008. [PubMed: 17600854]
10. Taber JM, Aspinwall LG, Kohlmann W, et al.: Parental preferences for CDKN2A/p16 testing of minors. Genet Med 12 (12): 823-38, 2010. [PubMed: 21045708]
11. Shuk E, Burkhalter JE, Baguer CF, et al.: Factors associated with inconsistent sun protection in first-degree relatives of melanoma survivors. Qual Health Res 22 (7): 934-45, 2012. [PMC free article: PMC4057020] [PubMed: 22645220]
12. Bergenmar M, Brandberg Y: Sunbathing and sun-protection behaviors and attitudes of young Swedish adults with hereditary risk for malignant melanoma. Cancer Nurs 24 (5): 341-50, 2001. [PubMed: 11605704]
13. Manne S, Fasanella N, Connors J, et al.: Sun protection and skin surveillance practices among relatives of patients with malignant melanoma: prevalence and predictors. Prev Med 39 (1): 36-47, 2004. [PubMed: 15207984]
14. Azzarello LM, Dessureault S, Jacobsen PB: Sun-protective behavior among individuals with a family history of melanoma. Cancer Epidemiol Biomarkers Prev 15 (1): 142-5, 2006. [PubMed: 16434600]
15. Glenn BA, Bastani R, Chang LC, et al.: Sun protection practices among children with a family history of melanoma: a pilot study. J Cancer Educ 27 (4): 731-7, 2012. [PubMed: 22610837]
16. Newton Bishop JA, Gruis NA: Genetics: what advice for patients who present with a family history of melanoma? Semin Oncol 34 (6): 452-9, 2007. [PubMed: 18083368]
17. Loescher LJ, Crist JD, Cranmer L, et al.: Melanoma high-risk families' perceived health care provider risk communication. J Cancer Educ 24 (4): 301-7, 2009. [PMC free article: PMC6204128] [PubMed: 19838889]
18. Christensen KD, Roberts JS, Shalowitz DI, et al.: Disclosing individual CDKN2A research results to melanoma survivors: interest, impact, and demands on researchers. Cancer Epidemiol Biomarkers Prev 20 (3): 522-9, 2011. [PMC free article: PMC3833711] [PubMed: 21307304]
19. Geller AC, Emmons KM, Brooks DR, et al.: A randomized trial to improve early detection and prevention practices among siblings of melanoma patients. Cancer 107 (4): 806-14, 2006. [PubMed: 16832795]
20. Manne S, Jacobsen PB, Ming ME, et al.: Tailored versus generic interventions for skin cancer risk reduction for family members of melanoma patients. Health Psychol 29 (6): 583-93, 2010. [PMC free article: PMC3058834] [PubMed: 21090893]
21. Geller AC, Emmons K, Brooks DR, et al.: Skin cancer prevention and detection practices among siblings of patients with melanoma. J Am Acad Dermatol 49 (4): 631-8, 2003. [PubMed: 14512908]
22. Azzarello LM, Jacobsen PB: Factors influencing participation in cutaneous screening among individuals with a family history of melanoma. J Am Acad Dermatol 56 (3): 398-406, 2007. [PubMed: 17184873]
23. Coups EJ, Manne SL, Jacobsen PB, et al.: Skin surveillance intentions among family members of patients with melanoma. BMC Public Health 11: 866, 2011. [PMC free article: PMC3248224] [PubMed: 22082038]
24. Kasparian NA, McLoone JK, Meiser B, et al.: Skin cancer screening behaviours among individuals with a strong family history of malignant melanoma. Br J Cancer 103 (10): 1502-9, 2010. [PMC free article: PMC2990585] [PubMed: 20978504]
25. Bergenmar M, Hansson J, Brandberg Y: Family members' perceptions of genetic testing for malignant melanoma--a prospective interview study. Eur J Oncol Nurs 13 (2): 74-80, 2009. [PubMed: 19179113]
26. Glanz K, Volpicelli K, Kanetsky PA, et al.: Melanoma genetic testing, counseling, and adherence to skin cancer prevention and detection behaviors. Cancer Epidemiol Biomarkers Prev 22 (4): 607-14, 2013. [PMC free article: PMC3617083] [PubMed: 23392000]
27. Aspinwall LG, Leaf SL, Dola ER, et al.: CDKN2A/p16 genetic test reporting improves early detection intentions and practices in high-risk melanoma families. Cancer Epidemiol Biomarkers Prev 17 (6): 1510-9, 2008. [PubMed: 18559569]
28. Aspinwall LG, Leaf SL, Kohlmann W, et al.: Patterns of photoprotection following CDKN2A/p16 genetic test reporting and counseling. J Am Acad Dermatol 60 (5): 745-57, 2009. [PubMed: 19278751]
29. Aspinwall LG, Taber JM, Leaf SL, et al.: Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome. Psychooncology 22 (2): 276-89, 2013. [PubMed: 23382133]
30. Aspinwall LG, Taber JM, Leaf SL, et al.: Melanoma genetic counseling and test reporting improve screening adherence among unaffected carriers 2 years later. Cancer Epidemiol Biomarkers Prev 22 (10): 1687-97, 2013. [PMC free article: PMC3837428] [PubMed: 23950214]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of skin cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewers for Genetics of Skin Cancer are:

• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Joanne Marie Jeter, MD (Huntsman Cancer Institute at University of Utah)
• Kelly Carter Nelson, MD, FAAD (M.D. Anderson Cancer Center at University of Texas)
• Suzanne C. O'Neill, PhD (Georgetown University)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
• Charite Ricker, MS, CGC (University of Southern California)
• Amanda Ewart Toland, PhD, FACMG (The Ohio State University)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Skin Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/skin/hp/skin-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389333]

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