Medical Policy

Policy Num:      11.003.036
Policy Name:    Genetic Testing for Familial Cutaneous Malignant Melanoma
Policy ID:          [11.003.036]  [Ac / B / M- / P-]  [2.04.44]

Last Review:      April 15, 2024
Next Review:      April 20, 2025

Related Policies: 

11.003.030 - Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)

11.003.022- Genetic Testing for Li-Fraumeni Syndrome

11.003.097 - Gene Expression Profiling for Cutaneous Melanoma

11.003.011 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)

11.003.016 - Genetic Testing for PTEN Hamartoma Tumor Syndrome

Germline Genetic Testing for Familial Cutaneous Malignant Melanoma (CDKN2A, CDK4)

summary

Description

Cutaneous melanoma is the third most common type of skin cancer, but the most lethal. Some cases of cutaneous malignant melanoma are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of the disease and in unaffected individuals in a high-risk family.

Summary of Evidence

For individuals who have cutaneous malignant melanoma and a family history of this disease who receive genetic testing for genes associated with familial cutaneous malignant melanoma, the evidence includes genetic association studies measuring prevalence of variants in certain genes among those with cutaneous malignant melanoma. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of melanoma patients, which involves surveillance and education on sun avoidance behaviors, does not change based on genetic variants identified in genes associated with familial cutaneous malignant melanoma; therefore, clinical utility is lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic and in a family at high-risk of developing cutaneous malignant melanoma who receive genetic testing for genes associated with familial cutaneous malignant melanoma, the evidence includes genetic association studies correlating variants in certain genes and the risk of developing cutaneous malignant melanoma. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of individuals considered high-risk for cutaneous malignant melanoma focuses on the reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. Some guidelines recommend specific screening intervals and modalities for CDKN2A variant carriers; however, these screening strategies have not been demonstrated to improve health outcomes in CDKN2A carriers; therefore, clinical utility is lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Genetic testing to select patients with melanoma for targeted therapy is addressed separately in evidence review 11.003.011.

OBJECTIVE

The objective of this evidence review is to evaluate the clinical validity and clinical utility of genetic testing of individuals with or at high-risk for familial cutaneous malignant melanoma and to determine if its use improves the net health outcome.

POLICY statement

Genetic testing for genes associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational (see Policy Guidelines).

POLICY GUIDELINES

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organisation, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”- to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to Report on Variants Found in DNA

Table PG2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Hereditary Cancer Syndromes and Screening Recommendations

Genetic susceptibility for melanoma can be a component in other hereditary cancer syndromes and therefore risk assessment and screening guidelines related to other cancers may be relevant to consider. See 11.003.030, 11.003.016, and 11.003.022.

NCCN v3.2024 guidelines for genetic/familial high-risk assessment in breast, ovarian, and pancreatic cancer recommend comprehensive skin examination by a dermatologist supplemented with biannual total body photography and dermoscopy for CDKN2A variant carriers. The publication referenced in the guidelines to support the recommendation is a review article that does not provide evidence that biannual total body photography and dermoscopy improves outcomes.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing. Genetic testing for genes associated with cutaneous malignant melanoma will likely be performed at specialty laboratories.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

Genetics of Cutaneous Malignant Melanoma

A genetic predisposition to cutaneous malignant melanoma is suspected in specific clinical situations: (1) melanoma has been diagnosed in multiple family members; (2) multiple primary melanomas have been identified in a single patient; and (3) early age of onset. A positive family history of melanoma is the most significant risk factor; it is estimated that approximately 10% of melanoma cases report a first- or second-degree relative with melanoma. Although some of the familial risk may be related to shared environmental factors, 3 principal genes involved in cutaneous malignant melanoma susceptibility have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21, encodes proteins that act as tumor suppressors. Variants in this gene can alter the tumor suppressor function. The second gene, cyclin-dependent kinase 4 (CDK4), is an oncogene located on chromosome 12q13 and has been identified in about 6 families worldwide. A third gene, not fully characterized, maps to chromosome 1p22.

Some common allele(s) are associated with increased susceptibility to cutaneous malignant melanoma but have low-to-moderate penetrance. One gene of moderate penetrance is the melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for cutaneous malignant melanoma. This gene is associated with fair complexion, freckles, and red hair, all risk factors for cutaneous malignant melanoma. Variants in MC1R also modify the cutaneous malignant melanoma risk in families with CDKN2A variants.^1,

In 2012, Ward et al reviewed the literature on germline melanoma susceptibility and concluded that in addition to the 2 rare, high-penetrance variants (CDKN2A and CDK4), there are potentially many single nucleotide polymorphisms which have small effects and low penetrance.^2,

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Melaris® (Myriad Genetics) and other CDKN2A tests are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

RATIONALE

This evidence review was created in September 2005 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through February 26, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Testing Individuals with Cutaneous Malignant Melanoma and Family History of this Disease

Clinical Context and Test Purpose

The purpose of genetic testing of individuals with cutaneous malignant melanoma and family history of the disease is to identify variants in genes associated with familial cutaneous malignant melanoma to inform management decisions and potentially inform the decision to test asymptomatic family members for variants associated with familial cutaneous malignant melanoma.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with cutaneous malignant melanoma and a family history of the disease.

The incidence of CDKN2A disease-associated variants in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A disease-associated variant. Variants are also infrequent in those with an early age of onset or those with multiple primary melanomas.^3, However, the incidence of CDKN2A disease-associated variants increases with a positive family history; CDKN2A disease-associated variants will be found in 5% of families with first-degree relatives, rising to 20% to 40% in patients with 3 or more affected first-degree relatives.^4, Variant detection rates of the CDKN2A gene are generally estimated to be 20% to 25% in hereditary cutaneous malignant melanoma but can vary between 2% and 50%, depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A disease-associated variant are available.^5,6,

Interventions

The test being considered is genetic testing for gene variants associated with cutaneous malignant melanoma.

Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

In 2012, Badenas et al suggested several parameters to guide genetic testing for melanoma: in countries with a low to medium incidence of melanoma, genetic testing should be offered to families with 2 cases of melanoma or to an individual with 2 primary melanomas (the rule of 2); in countries with a high incidence of melanoma, genetic testing should be offered to families with 3 cases of melanoma, or to an individual with 3 primary melanomas (the rule of 3).^7, In 2017, Delaunay et al suggested a modification to the recommendations by Badenas et al (2012). In countries with a low to medium incidence of melanoma, Delaunay et al (2017) proposed that the rule of 2 should guide genetic testing only if there is an individual with melanoma before the age of 40, otherwise the rule of 3 should apply.^8,

Comparators

The following practice is currently being used: standard clinical management without genetic testing. In individuals with melanoma, surveillance and follow-up decisions are guided by the individual's melanoma staging.

Outcomes

The potential beneficial outcomes of primary interest would be improvements in overall survival and disease-specific survival.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to unnecessary clinical management changes or unnecessary cascade testing for asymptomatic family members. False-negative test results can lead to the absence of clinical management changes or lack of testing for asymptomatic family members.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

One issue common to genetic testing for any cancer susceptibility is determining the clinical significance of individual variants. For example, variants in the CDKN2A gene can occur along its entire length, and some of these variants are benign. Interpretation will improve as more data accumulate on the clinical significance of individual variants in families with a known hereditary pattern of melanoma. However, the penetrance of a given variant will also affect its clinical significance, particularly because the penetrance of CDKN2A variants may vary with ethnicity and geographic location.^3,4, For example, exposure to sun and other environmental factors, as well as behavior and ethnicity, may contribute to penetrance. In 2002, Bishop et al estimated that the calculated risk of developing melanoma before age 80 years in carriers of CDKN2A variants ranged from 58% in Europe to 91% in Australia.^9,

Interpretation of a negative test is another issue. CDKN2A variants are found in less than half of those with a strong family history of melanoma. Therefore, additional melanoma predisposition genes are likely to exist, and patients with a strong family history with normal test results must not be falsely reassured that they are not at increased risk.^3, In a survey of individuals considered high-risk for melanoma, Branstrom et al (2012) reported that those with variant-negative test results erroneously believed that they had a lower risk of developing melanoma and practiced fewer preventive behaviors.^10,

Observational Studies

CDKN2A and CDK4 Studies

Table 1 summarizes rates of CDKN2A and CDK4 variants detected among patients with melanoma in various countries.

Harland et al (2014) conducted a case-control study on patients with melanoma from Australia, Spain, and the United Kingdom.^11,CDKN2A variant rates for each of the populations were similar (Table 1). Case-control analyses showed that the strongest predictor of carrying a variant was having multiple primaries (odds ratio [OR], 5.4; 95% confidence interval [CI], 2.5 to 11.6; 3 primaries, OR, 32.4; 95% CI, 14.7 to 71.2). Another predictor of carrying a variant is having a strong family history of melanoma (having 1 relative, OR, 3.8; 95% CI, 1.9 to 7.5; and having 2 or more relatives, OR, 23.2; 95% CI, 11.3 to 47.6).

Potrony et al (2014) measured the rate of CDKN2A variants among patients in Spain with sporadic multiple primary melanoma and familial melanoma.^12, Variant rates are presented in Table 1.

Bruno et al (2016) reported on the multiMEL study, in which genetic testing for CDKN2A and CDK4 variants were performed on 587 consecutive patients with multiple primary melanoma and 587 consecutive patients with single primary melanoma.^13, Rates of the variants are presented in Table 1. Subgroup analyses by familial versus sporadic melanoma showed that among patients with familial multiple primary melanoma and familial single primary melanoma, the mutation rates were 44.4% and 24.6%, respectively, compared with sporadic multiple primary melanoma and sporadic single primary melanoma variant rates of 10.8% and 2.1%, respectively.

Di Lorenzo et al (2016) observed 400 patients with cutaneous malignant melanoma for a 6-year period at an Italian university.^14, Forty-eight patients met the criteria of the Italian Society of Human Genetics for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 variants. Genetic testing revealed that none of the families carried variants in the CDK4 gene and only 1 patient harbored the rare CDKN2A p.R87W variant (Table 1). This low detection rate compared with other European countries and Australia could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian populations, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate-/low-penetrance susceptibility genes, which, together with environmental factors (eg, latitude, sun exposure), could determine the occurrence of melanoma.

Mangas et al (2016) measured the rate of CDKN2A variants among individuals considered high-risk for melanoma, defined as families with at least 2 cases of melanoma or individuals with multiple melanomas.^15, A total of 57 individuals were tested, 41 of which were considered the index cases. Of the 41, a CDKN2A variant was identified in 4 index cases (Table 1).

Puig et al (2016) conducted genetic testing for CDKN2A variants among patients with melanoma in Latin America and Spain.^16, Table 1 shows the variant rates among patients with familial melanoma. The CDKN2A variant rates were lower among patients in Latin America and Spain with sporadic multiple primary melanoma, 10.0% and 8.5%, respectively.

Artomov et al (2017) assessed the rate of rare genetic variants including CDKN2A among patients with familial cutaneous melanoma (N=273) in the United States and Greece.^17, A validation set utilizing case-matched European controls against data obtained from The Cancer Genome Atlas melanoma cohort (N=379) confirmed a statistically significant association for the CDKN2A variant (p=.009).

Gironi et al (2018) conducted genetic testing in Italian families prone to cutaneous melanoma to elucidate distinctive clinical and histological features of melanomas in CDKN2A mutation carriers.^18, Three hundred patients with cutaneous melanoma were enrolled and interviewed about their personal and family history of cutaneous melanoma and other cancers. Specifically, patients were eligible for genotyping if they had a histologically proven diagnosis of 1 or more cutaneous melanoma and met at least 1 of the following inclusion criteria: 1) cutaneous melanoma diagnosis at ≤40 years of age; 2) multiple primary melanoma; 3) family history of cutaneous melanoma; and/or 4) personal and/or family history of non-cutaneous cancers suggestive of familial cancer syndrome related to germline mutations of CDKN2A, CDK4, MITF, and BAP1 genes. Genotyping revealed 100 patients with wildtype CDKN2A genes and 32 patients with CDKN2A variants that were subsequently analyzed according to histological and clinical features. The wildtype group did not significantly differ from the CDKN2A mutation-positive group with respect to phototype (p=.759) or number of total common melanocytic nevi (p=.131). However, a personal history of previously excised dysplastic nevi was more frequent among CDKN2A variant-positive patients compared to wildtype (62.5% vs. 26%; p=<.001). A positive family history of cutaneous melanoma and/or pancreatic cancer was detected in 90.6% of mutation-positive patients compared to 37% of the wildtype group (p<.001). This significance was maintained for cutaneous melanoma or pancreatic cancer, individually (78.1% vs. 29%; p<.001 and 34.4% vs. 10%; p<.001). There were 54 (41%) patients in this study with at least 1 family member with a history of cutaneous melanoma. Among these patients, 25/54 (46.3%) carried a CDKN2A germline mutation. There were 21 (16%) patients with a family history of pancreatic cancer. Among these patients, 11/21 (52.4%) carried a CDKN2A germline mutation. Patients with a CDKN2A germline mutation developed a statistically significant higher number of multiple primary melanomas compared to the wildtype group (mean, 1.88 vs. 1.18; p<.001). However, while most patients in both genotype groups developed 2 primary melanomas (61% CDKN2A, 87.5% wildtype), 3 or 4 multiple primary melanomas were observed more frequently in patients with a CDKN2A mutation. All CDKN2A carriers were found to develop superficial spreading melanomas whereas wildtype patients generated mostly nodular melanomas or lentigo maligna and lentigo maligna melanomas (p=.006). There was no significant difference in CDKN2A status with respect to meeting inclusion criteria for sentinel node biopsy (15.6% CDKN2A, 22% wildtype; p=.302). Additionally, 0/5 (0%) patients who underwent the procedure with a CDKN2A variant showed metastases compared to 4/22 (18.2%) of wildtype patients.

De Simone et al (2020) conducted a retrospective review of melanoma predisposition variants (eg, CDKN2A, CDK4) in 888 patients with melanoma from Central Italy.^19, Overall, the study included 309 patients with multiple primary melanomas, 435 patients with familial melanoma, and 144 cases with both multiple primary melanomas and familial melanoma. Table 1 summarizes the CDKN2A variant rate, which includes variants of unknown significance.

Pissa et al (2021) conducted genetic testing for CDKN2A variants among 403 Swedish families between 2015-2020.^20, Included families had 3 or more cases of melanoma and/or pancreatic cancer, 2 melanomas in first-degree relatives with the youngest case occurring before age 55, or individuals with 3 or more multiple primary melanomas, with the first occurring before age 55. A total of 33 families (8.2%) were found to have CDKN2A pathogenic variants. Frequencies of CDKN2A pathogenic variants ranged from 0.9% in families with only 2 melanomas to 43.2% in families with 3 or more melanoma cases and pancreatic cancer. The frequency of CDKN2A variants ranged from 2.1% to 16.5% in families where the youngest case occurred after age 55 or before age 35 (p=.04). Families with CDKN2A pathogenic variants had a higher rate of melanoma-related mortality (37.6% versus 10.0%; p<.001). The authors concluded that these findings may help inform selection criteria to guide genetic testing for familial melanoma.

Table 1. Presence of CDKN2A Variants in Patients with Melanoma

^a Includes variants of unknown significance.
^b Based on familial incidence.

MC1R Studies

Ghiorzo et al (2012) studied 49 CDKN2A variant-positive and 390 CDKN2A variant-negative Italian patients with cutaneous melanoma.^21,MC1R (melanocortin 1 receptor gene) variants were associated with increased odds of melanoma only in CDKN2A variant-negative patients in a dose-dependent fashion: the OR for 1 high-risk allele was 1.5 (95% CI, 1.1 to 2.0); the odds for 2 high-risk alleles was 2.5 (95% CI, 1.7 to 3.7). In multivariate logistic regression, the effects of MC1R variants were statistically significant in most CDKN2A variant-negative subgroups and a few variant-positive subgroups defined by phenotype (eye and hair color, skin complexion and phototype, presence or absence of freckles or atypical nevi, total nevus count), sun exposure, and history of severe sunburn. In contrast, first-degree family history of cutaneous melanoma increased the odds of developing melanoma in both variant-positive (OR, 71.2; 95% CI, 23.0 to 221.0) and variant-negative (OR, 5.3; 95% CI, 2.0 to 14.3) patients, although the uncertainty in the estimates of association was considerable. The family history of cutaneous nevi (at least 1 first-degree relative with >10 nevi and/or atypical nevi) increased the odds of melanoma in variant-positive cases only (OR, 2.44; 95% CI, 1.3 to 4.5). This finding underscores the significance of nongenetic factors (eg, sun exposure, history of severe sunburn) for development of melanoma and the complexity of interpreting a positive family history.

Kanetsky et al (2010) described the associations between MC1R variants and melanoma in a U.S. population and investigated whether the genetic risk is modified by pigmentation characteristics and sun exposure.^22, The study population included melanoma patients (n=960) and controls (n=396) who self-reported phenotypic characteristics and sun exposure information. Logistic regression was used to estimate associations between high- and low-risk MC1R variants and melanoma, overall and within phenotypic and sun exposure groups. Carriage of 2 low-risk, or any high-risk MC1R variants, was associated with increased risk of melanoma (low-risk OR, 1.7; 95% CI, 1.0 to 2.8; high-risk OR, 2.2; 95% CI, 1.5 to 3.0). However, the risk was noted to be stronger in or limited to people with protective phenotypes and limited sun exposure, such as those who tanned well after repeated sun exposure (OR, 2.4), had dark hair (OR, 2.4), or had dark eyes (OR, 3.2). The authors concluded that MC1R genotypes provided information about melanoma risk in those individuals who would not be identified as high-risk based on their phenotypes or exposures alone. How this information impacts patient care and clinical outcomes are unknown.

Two subsequent studies in southern European populations examined further the association between MC1R variants and melanoma. In 2012, Ibarrola-Villava et al conducted a case-control study in 3 sample populations from France, Italy, and Spain.^23, Susceptibility genotypes in 3 genes involved in pigmentation processes were examined in 1,639 melanoma patients (15% familial) and 1342 controls. MC1R variants associated with red hair color were successfully genotyped in 85% of cases and 93% of controls. (Two other genes not associated with familial cutaneous melanoma-TYR, which encodes a tyrosinase, and SLC45 A2, which encodes a melanosome enzyme were also studied). In univariate logistic regression analysis, MC1R red hair color variants were significantly associated with the odds of developing melanoma in a dose-dependent fashion: the OR for 1 allele was 2.2 (95% CI, 1.9 to 2.6); the odds for 2 alleles was 5.0 (95% CI, 2.8 to 8.9). In an analysis stratified by self-reported phenotype, these variants were statistically associated with increased odds of melanoma not only in individuals with fair phenotype (eye, hair, and skin color) but also in those with dark/olive phenotype. The authors suggested that MC1R genotyping to identify elevated risk in southern European patients considered not at risk based on phenotype alone warranted further investigation.

Cust et al (2012) classified 565 patients with invasive cutaneous malignant melanoma diagnosed between 18 and 39 years of age, 518 sibling controls, and 409 unrelated controls into MC1R categories defined by the presence of high-risk or other alleles.^24, Compared with sibling controls, 2 MC1R high-risk alleles (R151C, R160W) were associated with increased odds of developing melanoma (R151C OR, 1.7; 95% CI, 1.1 to 2.6; R160W OR, 2.0; 95% CI, 1.2 to 3.2), but these associations were no longer statistically significant in analyses adjusted for pigmentation, nevus count, and sun exposure. Compared with unrelated controls, only the R151C high-risk allele was associated with increased odds of developing melanoma in the adjusted analysis. There was no association between other MC1R alleles (not considered high-risk) and the odds of developing melanoma in unadjusted or adjusted analyses.

Multiple Gene Study

Cust et al (2018) used the data from 2 large case-control studies to assess the incremental contribution of gene variants to risk prediction models using traditional phenotype and environmental factors.^25, Data from 1,035 cases and controls from an Australian study and 1,460 cases and controls from a United Kingdom study were used in the analyses. The logistic regression models contained the following variables: presence of 45 single nucleotide polymorphisms (among 21 genes); family history of melanoma; hair color; nevus density; nonmelanoma skin cancer; blistering sunburn as a child; sunbed use; freckling as an adult; eye color; and sun exposure hours on weekends and vacation. When polygenic risk scores were added to the model with traditional risk factors, the area under the receiving operator curve increased by 2.3% for the Australia population and 2.8% for the United Kingdom population. The MC1R gene variants, which are related to pigmentation, were responsible for most of the incremental improvement in the risk prediction models.

Systematic Reviews

In a meta-analysis of 145 genome-wide association studies, Chatzinasiou et al (2011) identified 8 independent genetic loci as associated with a statistically significant risk of cutaneous melanoma, including 6 with strong epidemiological credibility (MC1R, TYR, TYRP1, SLC45A2, ASIP/PIGU/MYH7B, CDKN2A/MTAP).^26,

Williams et al (2011) conducted a literature search through October 2009 and identified 20 studies providing data on 25 populations to include in a meta-analysis of MC1R variants and melanoma. The meta-analysis found red hair color variants on the MC1R gene to be associated with the highest risk of melanoma, but non-red hair color variants also were associated with an increased risk of melanoma.^27,

Section Summary: Clinically Valid

Studies measuring CDKN2A and CDK4 variants among patients with melanoma report rates between 2% and 24%, depending on the country of origin, type of melanoma (familial or sporadic), and number of primaries. Clinical sensitivity of genetic testing for genes associated with familial cutaneous malignant melanoma is difficult to ascertain due to differences in gene penetrance, variant interpretation, study populations, sun exposure, and preventive measures. These studies have not provided evidence that there is a clinically valid association between genetic variants and familial cutaneous malignant melanoma.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

Although genetic testing for CDKN2A variants is recognized as an important research tool, its clinical use will depend on how results of the genetic analysis can be used to improve patient management and health outcomes. Currently, management of patients considered high-risk for malignant melanoma focuses on the reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions.

If an affected individual tests positive for a CDKN2A variant, the individual may be at increased risk for a second primary melanoma compared with the general population. However, limited and protected sun exposure and increased surveillance would be recommended to any patient with malignant melanoma, regardless of the presence of a CDKN2A variant. A positive result would establish a familial variant and permit targeted testing in the rest of the family. A positive variant in an affected family member increases the likelihood of its clinical significance if detected in another family member. However, a negative test is not interpretable, as a negative result does not necessarily indicate a decreased risk for melanoma.

Published data on genetic testing of the CDKN2A and CDK4 genes have focused on the underlying genetics of hereditary melanoma, identification of variants in families at high-risk of melanoma, and risk of melanoma in those harboring these variants. One publication (2007) cautioned that differences in melanoma risk across geographic regions justify the need for studies in individual countries before counseling should be considered.^28,

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Currently, no inferences can be drawn about the usefulness of testing individuals with melanoma who have a family history of the disease.

Section Summary: Testing Individuals with Cutaneous Malignant Melanoma and Family History of this Disease

Direct evidence of the clinical utility of genetic testing in individuals with melanoma and a family history of the disease is lacking. While genetic variants associated with increased risk for developing melanoma have been identified, changes in clinical management and improved health outcomes as a result of genetic testing for individuals with melanoma is uncertain. Patients with melanoma, regardless of variant status, will receive instructions on recurrence preventive measures in regards to sun avoidance techniques.

For individuals who have cutaneous malignant melanoma and a family history of this disease who receive genetic testing for genes associated with familial cutaneous malignant melanoma, the evidence includes genetic association studies measuring prevalence of variants in certain genes among those with cutaneous malignant melanoma. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of melanoma patients, which involves surveillance and education on sun avoidance behaviors, does not change based on genetic variants identified in genes associated with familial cutaneous malignant melanoma; therefore, clinical utility is lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Testing Asymptomatic Individuals in a Family at High-Risk of Developing Cutaneous Malignant Melanoma

Clinical Context and Test Purpose

The purpose of genetic testing of asymptomatic individuals in a family at high-risk of developing cutaneous malignant melanoma is to identify variants in genes associated with melanoma for increased surveillance to potentially detect disease at an earlier, more treatable stage.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is asymptomatic individuals in a family at high-risk of developing cutaneous malignant melanoma.

Familial cutaneous malignant melanoma has been described in families in which either 2 first-degree relatives are diagnosed with melanoma or a family with 3 melanoma patients, irrespective of the degree of relationship.^29, Others have defined familial cutaneous malignant melanoma as having at least 3 (first-, second-, or third-degree) affected members or 2 affected family members in which at least 1 was diagnosed before age 50 years, or pancreatic cancer occurred in a first- or second-degree relative or 1 member had multiple primary melanomas.^30, Other malignancies associated with familial cutaneous malignant melanoma, specifically those associated with CDKN2A variants, have been described. The most pronounced associated malignancy is pancreatic cancer. Other associated malignancies include other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be involved in these families. In particular, germline BRCA2 gene variants have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.

Cutaneous malignant melanoma can occur either with or without a family history of multiple dysplastic nevi. Families with both cutaneous malignant melanoma and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome. This syndrome is difficult to define because there is no agreement on a standard phenotype, and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for cutaneous malignant melanoma. Initially, the phenotypes of atypical nevi and cutaneous malignant melanoma were thought to co-segregate in familial atypical multiple mole and melanoma syndrome families, leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that, in families with CDKN2A variants, some family members with multiple atypical nevi were noncarriers of the CDKN2A familial variant. Thus, the nevus phenotype cannot be used to distinguish carriers from noncarriers of cutaneous malignant melanoma susceptibility in these families.

Interventions

The test being considered is genetic testing for gene variants associated with cutaneous malignant melanoma.

Patient referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.

In 2012, Badenas et al suggested several parameters to guide genetic testing for melanoma: in countries with a low to medium incidence of melanoma, genetic testing should be offered to families with 2 cases of melanoma or to an individual with 2 primary melanomas (the rule of 2); in countries with a high incidence of melanoma, genetic testing should be offered to families with 3 cases of melanoma, or to an individual with 3 primary melanomas (the rule of 3).^7, In 2017, Delaunay et al suggested a modification to the recommendations by Badenas et al (2012). In countries with a low to medium incidence of melanoma, Delaunay et al (2017) proposed that the rule of 2 should guide genetic testing only if there is an individual with melanoma before the age of 40, otherwise the rule of 3 should apply.^8,

Comparators

The following practice is currently being used: standard clinical management without genetic testing. Personal and family history are used to guide melanoma screening decisions. For individuals in a family at high risk of melanoma, regular skin checks by trained health care providers, skin self-exams, and counseling on sun protective practices are recommended. Given the overlap between genetic susceptibility for melanoma and other cancers, there may be relevant recommendations for screening of other cancers (e.g., pancreatic, breast, colon).

Outcomes

The potential beneficial outcomes of primary interest would be improvements in overall survival and disease specific survival.

Potential harmful outcomes are those resulting from false-positive or false-negative test results. False-positive test results can lead to increased surveillance and preventive measures. False-negative test results can lead to an erroneous perception of lower risk, fewer preventive measures, and absence of increased surveillance.

The primary outcomes of interest are clinician-directed changes in patient management, including the initiation and frequency of monitoring and use of preventive measures.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Yang et al (2009) conducted a study to identify modifier genes for cutaneous malignant melanoma in cutaneous malignant melanoma-prone families with or without CDKN2A variants.^31, Investigators genotyped 537 individuals (107 cutaneous malignant melanoma) from 28 families (19 CDKN2A-positive, 9 CDKN2A-negative) for genes involved in DNA repair, apoptosis, and immune response. Analyses identified some candidate genes, such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9, and JAK3, associated with cutaneous malignant melanoma risk; after correction for multiple comparisons, IL9 remained significant. The effects of some genes were stronger in CDKN2A variant-positive families (BCL7A, IL9), and some were stronger in CDKN2A-negative families (BCL2L1). The authors considered these findings supportive of the hypothesis that common genetic variants in DNA repair, apoptosis, and immune response pathways may modify the risk of cutaneous malignant melanoma in cutaneous malignant melanoma-prone families, with or without CDKN2A variants.

Puntervoll et al (2013) described the phenotype of individuals with CDK4 variants in 17 melanoma families (209 individuals; 62 cases, 106 related controls, 41 unrelated controls).^32, The incidence of atypical nevi was higher in those with CDK4 variants (70% in melanoma patients vs. 75% in unaffected individuals) than in those without CDK4 variants (27%; p<.001). The distribution of eye or hair color did not differ statistically between CDK4 variant-positive individuals (with or without melanoma) and variant-negative family members. The authors concluded that “it is not possible to distinguish CDK4 melanoma families from those with CDKN2A variants based on phenotype.” As noted, the clinical significance of this genetic distinction is currently unclear.

Section Summary: Clinically Valid

Studies have indicated that the clinical sensitivity of genetic testing for genes associated with familial cutaneous malignant melanoma is difficult to ascertain due to differences in gene penetrance, variant interpretation, study populations, sun exposure, and preventive measures. For asymptomatic individuals in a family at high-risk for developing melanoma, identification of genetic variants provides minimal value in risk assessment due to the multifactorial nature of disease development and progression.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

If the asymptomatic individual is the first to be tested in the family (ie, no affected relative has been previously tested to define a familial variant), it is difficult to interpret the clinical significance of a variant, as described. The likelihood of clinical significance is increased if the identified variant is the same as that reported in other families, although the issue of penetrance is a confounding factor. If the asymptomatic individual has the same variant as an affected relative, then the patient is at high-risk for melanoma.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Several studies, described below, have reported changes in self- or objectively-reported changes in sun protective behaviors and attitudes as a result of genetic counseling and/or test reporting. However, no inferences can be drawn on the usefulness of testing asymptomatic individuals in a family at high-risk of developing cutaneous malignant melanoma as studies have not yet addressed improvements in key health outcomes and changes in clinician-directed patient management.

While some guidelines recommend specific melanoma screening intervals and modalities for CDKN2A variant carriers, these screening strategies have not been demonstrated to improve health outcomes in CDKN2A carriers.

Systematic Reviews

Primiero et al (2021) published 2 systematic reviews evaluating the impact of genetic testing in familial melanoma on primary and secondary preventative behaviors and psychosocial outcomes and attitudes.^33,34, Eight studies evaluating sun-protective behaviors were identified. Authors concluded that genetic testing has a modestly positive impact on sun-protective behaviors (eg, sunscreen use, sun-protective clothing, avoiding sun exposure and tanning) in high-risk individuals. These improvements were observed regardless of mutation carrier status, although higher adherence was observed in carriers. Twelve studies evaluating psychosocial outcomes and behaviors were identified. The authors found that generalized distress does not appear to be impacted by testing outcomes, carrier status, or personal history. However, melanoma-specific distress was associated with carrier status and/or personal history. Genetic risk assessment was not found to impact participants' perceived risk of subsequent melanomas.

Prospective Studies

Aspinwall et al (2008) reported on the short-term change in behavior among a small group of patients without melanoma who tested positive for the CDKN2A variant.^35, In this prospective study of 59 members of a CDKN2A variant-positive pedigree, behavioral assessments were made at baseline, immediately after CDKN2A test reporting and counseling, and at 1-month follow-up (42 participants). Across multiple measures, test reporting caused CDKN2A disease-associated variant carriers without a melanoma history to improve to the level of adherence reported by participants with a melanoma history. CDKN2A-positive participants without a melanoma history reported greater intention to obtain total body skin examinations, increased intentions and adherence to skin self-examination recommendations, and increased number of body sites examined at 1 month. In 2013, Aspinwall et al reported on outcomes for 37 (62%) patients of this cohort with 2-year follow-up.^36,37, Of the cohort available, 27 were unaffected noncarriers, 15 were unaffected carriers, and 18 were affected carriers. Anxiety, depression, and cancer-specific worry declined over 2 years, although baseline values were low and the declines are of uncertain clinical significance. Adherence to annual total body skin examinations and monthly skin self-examinations varied by carrier status; however, without a comparison group, it is not possible to attribute any change in adherence to the knowledge of test results.

Borroni et al (2017) offered CDKN2A variant testing and counseling to patients with familial atypical mole/multiple melanoma syndrome.^38, Variants were identified in 19 of the 92 patients. Of the 19 unrelated patients with a CDKN2A variant, 40 clinically healthy relatives were tested. Fifteen of the 40 relatives tested positive for the same variant as the relative with primary cutaneous melanoma. The 15 relatives underwent a complete dermatologic examination with dermoscopy. During a mean follow-up of 37 months (range, 4 to 53 months), none of the relatives developed primary cutaneous melanoma.

Aspinwall et al (2018) compared potential informational and motivational benefits from genetic testing for melanoma among individuals from high-risk families who were variant-positive (n=28), variant-negative (n=41), and unknown carrier status (n=45).^39, High-risk individuals were defined as those related to a patient with a known CDKN2A variant or those with a significant family history of melanoma (>3 cases) but no identified variant. All participants received genetic counseling, which included a risk estimate of developing melanoma during their lifetime. Outcomes, measured after 1 month and 1 year follow-up, included: feeling informed and prepared to manage risk; motivation to reduce sun exposure; motivation to perform screening; and negative/positive emotions about melanoma risk. Individuals who were tested (both variant-positive and variant-negative) reported feeling significantly more informed and prepared to manage risk compared to those not tested. All participants had low negative emotions concerning melanoma risk.

Stump et al (2018) provided genetic test reporting and counseling for melanoma risk in pediatric patients to assess effects on sun-protective behaviors and psychological harms.^40, Patients aged 10 to 15 years with a parent with a CDKN2A/p16 mutation, no personal history of melanoma, and no previous genetic testing for melanoma were eligible for the study. Twenty children enrolled and 2 withdrew prior to the 1-month follow-up visit, resulting in 18 participants from 11 families. Measures of protective behavior and distress were collected at baseline, 1 week, 1 month, and 1 year. Participants and their mothers were individually interviewed regarding the psychological and behavioral impact of genetic testing. CDKN2A carriers (n=9) and non-carriers (n=9) both reported significantly fewer sunburns and a greater proportion reported sun protection adherence between baseline and 1 year; results did not vary by mutation status. Anxiety symptoms were low post-disclosure, whereas depressive symptoms and cancer worry decreased.

Stump et al (2020) investigated whether genetic counseling and test reporting for CDKN2A carrier status promoted objective reductions in sun exposure.^41, Participants were recruited from 2 types of pedigrees: families with an identified CDKN2A mutation and families with a similar melanoma history but no identified CDKN2A mutation. Subjects from CDKN2A-positive families were derived from 3 kindreds, and accounted for 32 carriers and 46 noncarriers. No-test control subjects (n=50) were derived from 9 CDKN2A-negative families. The daily standard erythemal dose (SED; J/m²) of ultraviolet radiation (UVR) exposure was measured with a wrist-worn, battery-powered dosimeter over three 27-day periods. Complete dosimetry data was available for 75.8% of participants, with missing data due to technical issues, device loss, or device damage. The average number of days coded as "not worn" ranged from 7 to 10 days in each assessment period. Both carriers and no-test controls exhibited a significant decrease in UVR dose at 1 year compared to baseline (p<.01). No change from baseline was noted for noncarriers at any timepoint. However, these outcomes do not account for the use of sunscreen or sun-protective clothing. Skin pigmentation was assessed via reflectance spectroscopy, yielding a Melanin Index score in which higher scores represent greater melanin content. Measurements from the face and wrist were standardized to measurements obtained from non-exposed sites to account for differences in skin tone. Data from patients using artificial tanning products within a week of testing were excluded. Only carriers exhibited a significant decrease in skin pigmentation at the wrist at 1 year (p<.001). However, no corresponding changes in facial pigmentation were detected for any group. Both carriers and no-test controls self-reported fewer sunburns than non-carriers (p<.05). Noncarriers did not demonstrate changes in any measure of UVR exposure; however, daily UVR exposure was higher among noncarriers compared to no-test controls at baseline (p=.03). Despite the incorporation of propensity score matching in their statistical methods, the authors acknowledged that they cannot exclude yet-to-be identified confounding factors driving between-group differences in their non-equivalent control study design. The study did not assess key health outcomes such as melanoma incidence.

Retrospective Studies

In a retrospective case-control study, van der Rhee et al (2011) sought to determine whether a 25-year surveillance program of families with a Dutch founder mutation in CDKN2A (the p16-Leiden variant) permitted earlier identification of melanomas.^42, Characteristics of 40 melanomas identified in 35 unscreened index patients (before heredity was diagnosed) were compared with 226 melanomas identified in 92 relatives of those 35 melanoma patients who were later found to have the CDKN2A variant. Surveillance consisted of a minimum of an annual total skin evaluation, which became more frequent if melanoma was diagnosed. Melanomas diagnosed during surveillance were found to have a significantly lower Breslow thickness (median thickness, 0.50 mm) than melanomas identified in unscreened index patients (median thickness, 0.98 mm), signifying earlier identification with surveillance. However, only 53% of melanomas identified in the surveillance group were detected on regular screening appointments. Additionally, there was no correlation between length of screening intervals (for intervals <24 months) and melanoma tumor thickness at the time of diagnosis. The authors also noted that, despite understanding the importance of surveillance, patient noncompliance with surveillance recommendations still occurred

van der Rhee et al (2013) reported on a retrospective case-control study of 21 families with the CDKN2A p16-Leiden founder mutation.^43, This study investigated the yield of surveillance of first- and second-degree relatives of patients with melanoma (n=14 families) or with melanoma and pancreatic cancer (n=7 families). Overall, melanoma incidence rates were 9.9 per 1000 person-years (95% CI, 7.4 to 13.3 person-years) in first-degree relatives and 2.1 per 1000 person-years (95% CI, 1.2 to 3.8 person-years) in second-degree relatives. Compared with the general Dutch population, overall standardized morbidity ratios for melanoma were 101.0 (95% CI, 55.9 to 182.3) in first-degree relatives (observed, 45; expected, 0.76) and 12.9 (95% CI, 7.2 to 23.4) in second-degree relatives (observed, 11; expected, 0.53). Although the authors concluded that surveillance of second- (as well as first-) degree relatives from very high-risk melanoma families were justified based on these findings, it is unclear whether these findings apply to families without or with other CDKN2A variants. Further, because increased sun protection and surveillance are recommended for any member of a high-risk family, the clinical utility of the finding is uncertain.

Dalmasso et al (2018) conducted a retrospective case-control study to determine if there was an association between CDKN2A variants and survival among patients with melanoma.^44, From consecutive patients with the diagnosis of melanoma and genetic testing data from a single hospital, 106 variant-positive cases, and 199 variant-negative controls, matched by age and sex, were included in the analyses. The overall rate of deaths in both groups was 17%. Melanoma-specific mortality was 10.8% in the variant-positive group and 7.8% in the variant-negative group. There were no statistically significant differences in overall or melanoma-specific survival between the 2 groups.

Relevance, design, and conduct limitations of selected studies are summarized in Tables 2 and 3.

Table 2. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.; 5 Enrolled study populations do not reflect relevant diversity
^b Intervention key: 1. Classification thresholds not defined; 2. Version used unclear; 3. Not intervention of interest.
^c Comparator key: 1. Classification thresholds not defined; 2. Not compared to credible reference standard; 3. Not compared to other tests in use for same purpose.
^d Outcomes key: 1. Study does not directly assess a key health outcome; 2. Evidence chain or decision model not explicated; 3. Key clinical validity outcomes not reported (sensitivity, specificity, and predictive values); 4. Reclassification of diagnostic or risk categories not reported; 5. Adverse events of the test not described (excluding minor discomforts and inconvenience of venipuncture or noninvasive tests).
^e Follow-Up key: 1. Follow-up duration not sufficient with respect to natural history of disease (true-positives, true-negatives, false-positives, false-negatives cannot be determined).

Table 3. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (ie, convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

Section Summary: Testing Asymptomatic Individuals in a Family at High-Risk of Developing Cutaneous Malignant Melanoma

Direct evidence of the clinical utility of genetic testing in asymptomatic individuals in a family at high-risk for developing cutaneous malignant melanoma is lacking. Among the prospective studies, only one had an outcome of melanoma occurrence. None of the carriers developed melanoma, but the sample size was small and the duration of follow-up may not have been sufficient to detect disease development. While familial variants associated with increased risk for developing melanoma have been identified, net benefit of changes in clinical management a result of genetic testing for asymptomatic individuals is uncertain.

For individuals who are asymptomatic and in a family at high-risk of developing cutaneous malignant melanoma who receive genetic testing for genes associated with familial cutaneous malignant melanoma, the evidence includes genetic association studies correlating variants in certain genes and the risk of developing cutaneous malignant melanoma. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of individuals considered high-risk for cutaneous malignant melanoma focuses on the reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. Some guidelines recommend specific screening intervals and modalities for CDKN2A variant carriers; however, these screening strategies have not been demonstrated to improve health outcomes in CDKN2A carriers; therefore, clinical utility is lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Dermatology

In 2019, the American Academy of Dermatology published guidelines for the care and management of primary cutaneous melanoma.^45, Referral for genetic counseling and possible germline genetic testing for select patients with cutaneous melanoma was recommended for consideration with a level IIIC grade of evidence. The Work Group explained that "there is no strong evidence that genetic evaluation is either harmful or helpful." Criteria for cancer risk genetic counseling with possible multigene testing for patients with cutaneous melanoma include:

• A family history of invasive cutaneous melanoma or pancreatic cancer (≥3 affected members on 1 side of the family)

• Multiple primary invasive cutaneous melanomas (≥3), including 1 early-onset tumor (at age <45 years)

• A family history of mesothelioma, meningioma, and/or uveal melanoma and ≥1 melanocytic BAP1-mutated atypical intradermal tumor (MBAIT)

• ≥2 MBAITs

These 2019 guidelines are similar to standards previously established by the International Melanoma Genetics Consortium in 2009.^46,

American Society of Clinical Oncology

In an American Society of Clinical Oncology (ASCO) publication, Kefford et al (2002) noted that the sensitivity and specificity of tests for CDKN2A variants are not fully known.^47, Because interpreting genetic tests is difficult and because test results do not alter patient management, ASCO recommended that CDKN2A genetic testing should be performed only in clinical trials, for several reasons. These include a low likelihood of finding disease-associated variants in known melanoma susceptibility genes, uncertainty about the functionality and phenotypic expression of the trait among disease-associated variant carriers, and lack of proven melanoma prevention and surveillance strategies. Additionally, it was noted that all individuals with risk factors for cutaneous melanoma should follow programs of sun protection and skin surveillance, not just those considered high-risk due to family history.

In 2003,^48, and 2010,^49, ASCO issued policy statements on genetic and genomic testing for cancer susceptibility. Both statements recommended that, outside of a research setting, genetic testing for cancer susceptibility should only be offered when the following 3 criteria are met: (1) the individual being tested has a personal or family history suggestive of an underlying hereditary component; (2) the genetic test can be adequately interpreted; and (3) test results will guide diagnosis and management.

In 2010, ASCO updated its policy statement on genetic and genomic testing for cancer susceptibility.^49, ASCO recommended that “genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials.”

In 2015, ASCO commissioned another update to its policy statement on genetic and genomic testing for cancer susceptibility.^50, ASCO "affirms that it is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient's personal and/or family history."

National Comprehensive Cancer Network

Current (v.1.2024 ) National Comprehensive Cancer Network (NCCN) guidelines for cutaneous melanoma include the following follow-up recommendations:^51,

• “Consider genetic counseling referral for p16/CDKN2A mutation [variant] testing in the presence of 3 or more invasive melanomas, or a mix of invasive melanoma, pancreatic cancer, and/or astrocytoma diagnoses in an individual or family."

• "Multigene panel testing that includes CDKN2A is recommended for patients with invasive cutaneous melanoma who have a first-degree relative diagnosed with pancreatic cancer."

• "Testing for other genes that can harbor melanoma-predisposing mutations [e.g., MC1R, CDK4, TERT, MITF, PTEN, BRCA2, and BAP1] may be warranted."

Current (v.3.2024 ) NCCN guidelines for genetic/familial high-risk assessment in breast, ovarian, and pancreatic cancer state that for CDKN2A mutation carriers, "comprehensive skin examination by a dermatologist, supplemented with total body photography and dermoscopy is recommended biannually."^52,

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

NCT: national clinical trial; NR: not reported.
^a Denotes industry-sponsored or cosponsored trial.

REFERENCES

1. Pho L, Grossman D, Leachman SA. Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Curr Opin Oncol. Mar 2006; 18(2): 173-9. PMID 16462187
2. Ward KA, Lazovich D, Hordinsky MK. Germline melanoma susceptibility and prognostic genes: a review of the literature. J Am Acad Dermatol. Nov 2012; 67(5): 1055-67. PMID 22583682
3. Hayward NK. Genetics of melanoma predisposition. Oncogene. May 19 2003; 22(20): 3053-62. PMID 12789280
4. Kefford RF, Newton Bishop JA, Bergman W, et al. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium. J Clin Oncol. Oct 1999; 17(10): 3245-51. PMID 10506626
5. Niendorf KB, Goggins W, Yang G, et al. MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability. J Med Genet. Jun 2006; 43(6): 501-6. PMID 16169933
6. Wang W, Niendorf KB, Patel D, et al. Estimating CDKN2A carrier probability and personalizing cancer risk assessments in hereditary melanoma using MelaPRO. Cancer Res. Jan 15 2010; 70(2): 552-9. PMID 20068151
7. Badenas C, Aguilera P, Puig-Butillé JA, et al. Genetic counseling in melanoma. Dermatol Ther. 2012; 25(5): 397-402. PMID 23046018
8. Delaunay J, Martin L, Bressac-de Paillerets B, et al. Improvement of Genetic Testing for Cutaneous Melanoma in Countries With Low to Moderate Incidence: The Rule of 2 vs the Rule of 3. JAMA Dermatol. Nov 01 2017; 153(11): 1122-1129. PMID 28903138
9. Bishop DT, Demenais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. Jun 19 2002; 94(12): 894-903. PMID 12072543
10. 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. Nov 2012; 48(16): 3052-62. PMID 22726816
11. Harland M, Cust AE, Badenas C, et al. Prevalence and predictors of germline CDKN2A mutations for melanoma cases from Australia, Spain and the United Kingdom. Hered Cancer Clin Pract. 2014; 12(1): 20. PMID 25780468
12. Potrony M, Puig-Butillé JA, Aguilera P, et al. Increased prevalence of lung, breast, and pancreatic cancers in addition to melanoma risk in families bearing the cyclin-dependent kinase inhibitor 2A mutation: implications for genetic counseling. J Am Acad Dermatol. Nov 2014; 71(5): 888-95. PMID 25064638
13. Bruno W, Pastorino L, Ghiorzo P, et al. Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup. J Am Acad Dermatol. Feb 2016; 74(2): 325-32. PMID 26775776
14. Di Lorenzo S, Fanale D, Corradino B, et al. Absence of germline CDKN2A mutation in Sicilian patients with familial malignant melanoma: Could it be a population-specific genetic signature?. Cancer Biol Ther. 2016; 17(1): 83-90. PMID 26650572
15. Mangas C, Potrony M, Mainetti C, et al. Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF. Br J Dermatol. Nov 2016; 175(5): 1030-1037. PMID 27473757
16. Puig S, Potrony M, Cuellar F, et al. Characterization of individuals at high risk of developing melanoma in Latin America: bases for genetic counseling in melanoma. Genet Med. Jul 2016; 18(7): 727-36. PMID 26681309
17. Artomov M, Stratigos AJ, Kim I, et al. Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing. J Natl Cancer Inst. Dec 01 2017; 109(12). PMID 29522175
18. Gironi LC, Colombo E, Pasini B, et al. Melanoma-prone families: new evidence of distinctive clinical and histological features of melanomas in CDKN2A mutation carriers. Arch Dermatol Res. Dec 2018; 310(10): 769-784. PMID 30218143
19. De Simone P, Bottillo I, Valiante M, et al. A Single Center Retrospective Review of Patients from Central Italy Tested for Melanoma Predisposition Genes. Int J Mol Sci. Dec 11 2020; 21(24). PMID 33322357
20. Pissa M, Helkkula T, Appelqvist F, et al. CDKN2A genetic testing in melanoma-prone families in Sweden in the years 2015-2020: implications for novel national recommendations. Acta Oncol. Jul 2021; 60(7): 888-896. PMID 33945383
21. Ghiorzo P, Bonelli L, Pastorino L, et al. MC1R variation and melanoma risk in relation to host/clinical and environmental factors in CDKN2A positive and negative melanoma patients. Exp Dermatol. Sep 2012; 21(9): 718-20. PMID 22804906
22. Kanetsky PA, Panossian S, Elder DE, et al. Does MC1R genotype convey information about melanoma risk beyond risk phenotypes?. Cancer. May 15 2010; 116(10): 2416-28. PMID 20301115
23. Ibarrola-Villava M, Hu HH, Guedj M, et al. MC1R, SLC45A2 and TYR genetic variants involved in melanoma susceptibility in southern European populations: results from a meta-analysis. Eur J Cancer. Sep 2012; 48(14): 2183-91. PMID 22464347
24. Cust AE, Goumas C, Holland EA, et al. MC1R genotypes and risk of melanoma before age 40 years: a population-based case-control-family study. Int J Cancer. Aug 01 2012; 131(3): E269-81. PMID 22095472
25. Cust AE, Drummond M, Kanetsky PA, et al. Assessing the Incremental Contribution of Common Genomic Variants to Melanoma Risk Prediction in Two Population-Based Studies. J Invest Dermatol. Dec 2018; 138(12): 2617-2624. PMID 29890168
26. Chatzinasiou F, Lill CM, Kypreou K, et al. Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst. Aug 17 2011; 103(16): 1227-35. PMID 21693730
27. Williams PF, Olsen CM, Hayward NK, et al. Melanocortin 1 receptor and risk of cutaneous melanoma: a meta-analysis and estimates of population burden. Int J Cancer. Oct 01 2011; 129(7): 1730-40. PMID 21128237
28. Goldstein AM, Chaudru V, Ghiorzo P, et al. Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries. Int J Cancer. Aug 15 2007; 121(4): 825-31. PMID 17397031
29. de Snoo FA, Bergman W, Gruis NA. Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer. 2003; 2(2): 109-16. PMID 14574160
30. Casula M, Colombino M, Satta MP, et al. Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy. Eur J Cancer. Jan 2007; 43(1): 137-43. PMID 17055252
31. Yang XR, Pfeiffer RM, Wheeler W, et al. Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. Int J Cancer. Dec 15 2009; 125(12): 2912-7. PMID 19626699
32. Puntervoll HE, Yang XR, Vetti HH, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. Apr 2013; 50(4): 264-70. PMID 23384855
33. Primiero CA, Yanes T, Finnane A, et al. A Systematic Review on the Impact of Genetic Testing for Familial Melanoma I: Primary and Secondary Preventative Behaviours. Dermatology. 2021; 237(5): 806-815. PMID 33588421
34. Primiero CA, Yanes T, Finnane A, et al. A Systematic Review on the Impact of Genetic Testing for Familial Melanoma II: Psychosocial Outcomes and Attitudes. Dermatology. 2021; 237(5): 816-826. PMID 33508831
35. 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. Jun 2008; 17(6): 1510-9. PMID 18559569
36. Aspinwall LG, Taber JM, Leaf SL, et al. Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome. Psychooncology. Feb 2013; 22(2): 276-89. PMID 23382133
37. 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. Oct 2013; 22(10): 1687-97. PMID 23950214
38. Borroni RG, Manganoni AM, Grassi S, et al. Genetic counselling and high-penetrance susceptibility gene analysis reveal the novel CDKN2A p.D84V (c.251A T) mutation in melanoma-prone families from Italy. Melanoma Res. Apr 2017; 27(2): 97-103. PMID 28060055
39. Aspinwall LG, Stump TK, Taber JM, et al. Genetic test reporting of CDKN2A provides informational and motivational benefits for managing melanoma risk. Transl Behav Med. Jan 29 2018; 8(1): 29-43. PMID 29385581
40. Stump TK, Aspinwall LG, Kohlmann W, et al. Genetic Test Reporting and Counseling for Melanoma Risk in Minors May Improve Sun Protection Without Inducing Distress. J Genet Couns. Aug 2018; 27(4): 955-967. PMID 29349527
41. Stump TK, Aspinwall LG, Drummond DM, et al. CDKN2A testing and genetic counseling promote reductions in objectively measured sun exposure one year later. Genet Med. Jan 2020; 22(1): 26-34. PMID 31371819
42. van der Rhee JI, de Snoo FA, Vasen HFA, et al. Effectiveness and causes for failure of surveillance of CDKN2A-mutated melanoma families. J Am Acad Dermatol. Aug 2011; 65(2): 289-296. PMID 21570154
43. van der Rhee JI, Boonk SE, Putter H, et al. Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation. Cancer Epidemiol Biomarkers Prev. Oct 2013; 22(10): 1771-7. PMID 23897584
44. Dalmasso B, Pastorino L, Ciccarese G, et al. CDKN2A germline mutations are not associated with poor survival in an Italian cohort of melanoma patients. J Am Acad Dermatol. May 2019; 80(5): 1263-1271. PMID 30274933
45. Swetter SM, Tsao H, Bichakjian CK, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. Jan 2019; 80(1): 208-250. PMID 30392755
46. Leachman SA, Carucci J, Kohlmann W, et al. Selection criteria for genetic assessment of patients with familial melanoma. J Am Acad Dermatol. Oct 2009; 61(4): 677.e1-14. PMID 19751883
47. Kefford R. Clinical approach to genetic risk for melanoma. In: Perry M, ed. American Society of Clinical Oncology Educational Book. Baltimore: Lippincott Williams and Wilkins; 2002:436-445.
48. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. Jun 15 2003; 21(12): 2397-406. PMID 12692171
49. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. Feb 10 2010; 28(5): 893-901. PMID 20065170
50. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol. Nov 01 2015; 33(31): 3660-7. PMID 26324357
51. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma. Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed February 26, 2024.
52. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed February 27, 2024.

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