Health Library
Genetics Of Skin Cancer (PDQ®): Genetics - Health Professional Information [NCI]
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 Risk
More 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) 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 (which is sometimes referred to as cutaneous melanoma) is a less common type of skin cancer, but 5% to 10% of all melanomas arise in multiple-case families and can be inherited in an autosomal dominant fashion. Melanoma is the most lethal of the common skin cancers.
- Associated Genes and Syndromes
Several genes and hereditary syndromes are associated with the development of skin cancer:
- Basal cell carcinoma - Basal cell nevus syndrome (BCNS, caused by pathogenic variants in PTCH1 and PTCH2) is associated with increased BCC risk.
- Squamous cell carcinoma - Syndromes such as oculocutaneous albinism, epidermolysis bullosa, and Fanconi anemia are associated with increased SCC risk.
- Melanoma - CDKN2A is a major germline tumor suppressor gene that is associated with increased melanoma risk. Pathogenic variants in CDKN2A may account for 35% to 40% of all familial melanomas. Germline pathogenic variants in several other genes (i.e., CDK4, MITF, and BAP1) are also associated with increased melanoma risk.
An autosomal recessive disease, called xeroderma pigmentosum (XP), is associated with increased BCC, SCC, and melanoma risks.
Genome-wide association studies show promise for identifying common, low-penetrance susceptibility alleles for many complex diseases, including melanoma, but the clinical utility of these findings remains uncertain.
- Clinical Management
Risk-reducing strategies for individuals with an increased hereditary predispositions to skin cancer are similar to recommendations for those in the general population. These recommendations 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 Issues
Most 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 patients with melanoma, with mixed results. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.