Genetics of Skin Cancer (PDQ®) 4/4 —Health Professional Version - National Cancer Institute

Genetics of Skin Cancer (PDQ®)—Health Professional Version - National Cancer Institute

Genetics of Skin Cancer (PDQ®)–Health Professional Version

Rare Skin Cancer Syndromes

In This Section

• Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis
• Sebaceous Carcinoma
• Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)

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. Refer to Table 3, Basal Cell Carcinoma (BCC) Syndromes, for more information about BSS.

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 utilized 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. (Refer to the HLRCC section in the PDQ summary on Genetics of Kidney Cancer (RCC) for more information.)

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 Abstract]
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 Abstract]
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. [PUBMED Abstract]
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 Abstract]
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. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
9. Schwartz RA, Torre DP: The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol 33 (1): 90-104, 1995. [PUBMED Abstract]
10. Cohen PR, Kohn SR, Kurzrock R: Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med 90 (5): 606-13, 1991. [PUBMED Abstract]
11. Cerosaletti KM, Lange E, Stringham HM, et al.: Fine localization of the Nijmegen breakage syndrome gene to 8q21: evidence for a common founder haplotype. Am J Hum Genet 63 (1): 125-34, 1998. [PUBMED Abstract]
12. Mangold E, Pagenstecher C, Leister M, et al.: A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. J Med Genet 41 (7): 567-72, 2004. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
18. Adan F, Crijns MB, Zandstra WSE, et al.: Cumulative risk of skin tumours in patients with Lynch syndrome. Br J Dermatol : , 2018. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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. [PUBMED Abstract]

Psychosocial Issues in Familial Melanoma

In This Section

• Introduction
• Interest in and Uptake of Genetic Testing for Risk of Melanoma
  • Testing in children
• Risk Awareness and Risk Reduction in Individuals at Increased Familial Risk of Melanoma
  • Intervention studies
• Screening Behaviors in Individuals at Increased Familial Risk of Melanoma
  • Intervention studies
• Psychosocial Outcomes of Genetic Counseling and Genetic Testing

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] (Refer to the Melanoma Risk Assessment section of this summary for more information about clinical genetic testing for melanoma susceptibility.)

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 make a contribution 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.

Testing in children

Among 61 people tested for CDKN2A pathogenic variants (52.5% tested positive) from two large melanoma kindreds, most (75.4%) had children or grandchildren younger than 18 years and expressed interest in testing of minors (73.8%).[10] Among carriers of CDKN2Apathogenic variants, most (86.7%) wanted their children or grandchildren to be tested, and among noncarriers, half (50%) wanted testing for their own children or grandchildren. The most cited reason for testing children was to aid in risk awareness and to improve protection and screening behavior.

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.

Intervention studies

A few intervention studies have targeted knowledge about melanoma, sun protection, and screening in family members of melanoma patients. In one study among siblings, participants drawn from a clinic population were randomly assigned to an intervention that included telephone messages and tailored print materials about risk reduction and screening recommendations. The usual care group received a standard physician-practice recommendation that patients notify family members about their diagnosis. The intervention group showed improvements in knowledge about melanoma, confidence in seeing a dermatologist and having a screening examination, and greater improvements in skin self-examination practices compared with control participants after 12 months; both groups showed twofold increases in physician examinations after 12 months; there was no change in sunscreen behaviors in either group.[19]

In another study, 443 family members of melanoma patients were randomly assigned to either a generic or tailored intervention that consisted of three (untailored or tailored) print mailings and one (untailored or tailored) telephone counseling session. Overall, the tailored intervention group showed an almost twofold increase in frequency of total cutaneous skin examinations by a health care provider compared with the generic intervention. However, no differences were observed for skin self-examinations between intervention arms. In contrast to the previous study, which did not show improvements in sun protection habits,[19] participants in this study who received the tailored intervention were significantly more likely to report improvements in sun protection habits than were those who received the generic intervention.[20]

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 CDKN2Apathogenic 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]

Intervention studies

A few intervention studies have targeted knowledge about melanoma, sun protection, and screening in family members of melanoma patients. In one study among siblings, participants drawn from a clinic population were randomly assigned to an intervention that included telephone messages and tailored print materials about risk reduction and screening recommendations. The usual care group received a standard physician-practice recommendation that patients notify family members about their diagnosis. The intervention group showed improvements in knowledge about melanoma, confidence in seeing a dermatologist and having a screening examination, and greater improvements in skin self-examination practices compared with control participants after 12 months; both groups showed twofold increases in physician examinations after 12 months; there was no change in sunscreen behaviors in either group.[19]

In another study, 443 family members of melanoma patients were randomly assigned to either a generic or tailored intervention that consisted of three (untailored or tailored) print mailings and one (untailored or tailored) telephone counseling session. Overall, the tailored intervention group showed an almost twofold increase in frequency of total cutaneous skin examinations by a health care provider compared with the generic intervention. However, no differences were observed for skin self-examinations between intervention arms. In contrast to the previous study, which did not show improvements in sun protection habits,[19] participants in this study who received the tailored intervention were significantly more likely to report improvements in sun protection habits than were those who received the generic intervention.[20]

Psychosocial Outcomes of Genetic Counseling and Genetic Testing

A few small studies have examined distress and behavioral factors associated with CDKN2Atesting 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 (CDKN2Aand 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

1. de Snoo FA, Bergman W, Gruis NA: Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer 2 (2): 109-16, 2003. [PUBMED Abstract]
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 Abstract]
3. Hansen CB, Wadge LM, Lowstuter K, et al.: Clinical germline genetic testing for melanoma. Lancet Oncol 5 (5): 314-9, 2004. [PUBMED Abstract]
4. Bergman W, Gruis NA: Phenotypic variation in familial melanoma: consequences for predictive DNA testing. Arch Dermatol 143 (4): 525-6, 2007. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
8. Loescher LJ, Crist JD, Siaki LA: Perceived intrafamily melanoma risk communication. Cancer Nurs 32 (3): 203-10, 2009 May-Jun. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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 Abstract]
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. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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 Abstract]
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. [PUBMED Abstract]
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 Abstract]
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 Abstract]
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 Abstract]
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. [PUBMED Abstract]

Changes to This Summary (05/24/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Squamous Cell Carcinoma

Added text to state that the type of epidermolysis bullosa (EB) can be difficult to determine clinically, although genetic testing may aid in the classification. In one study of 91 probands with features of EB, a next-generation sequencing panel of 21 genes associated with different forms of EB or skin fragility syndromes was able to predict the subtype in 76 of 87 probands of undetermined subtype (cited Vahidnezhad et al. as reference 120). Similar multigene panels are clinically available for EB.

Revised text to state that skin cancer accounts for approximately 9% of tumors in the Bloom Syndrome Registry (cited Cunniff et al. as reference 198). Also revised text to state that skin cancers occur at an early age in this population, with a mean age of 31 years at the time of diagnosis.

Added Tamura et al. as reference 231.

Melanoma

Added text to state that a study of pediatric patients with melanoma in melanoma-prone families reported a significant increase in melanoma prevalence relative to the general population. In this series, 7 of 21 patients with CDKN2A pathogenic variants were diagnosed with multiple primary melanomas before age 20 years (cited Goldstein et al. as reference 59).

Added Walpole et al. as reference 111.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

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 who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Skin Cancer are:

• Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
• Joanne Marie Jeter, MD (The Ohio State University)
• Suzanne M. O'Neill, MS, PhD, CGC
• Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
• Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
• Amanda Ewart Toland, PhD, FACMG (The Ohio State University)
• Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
• Catharine Wang, PhD, MSc (Boston University School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

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]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

• Updated: May 24, 2019