|MP 2.04.44||Genetic Testing for Familial Cutaneous Malignant Melanoma|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/10:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
A genetic predisposition to cutaneous malignant melanoma (CMM) is suspected in specific clinical situations: 1) melanoma has been diagnosed in multiple family members; 2) multiple primary melanomas are identified in a single patient; and 3) in the case of 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 main genes involved in CMM susceptibility have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21 encodes proteins that act as tumor suppressors. Mutations at this site 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.
The incidence of CDKN2A mutations 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 mutation. Mutations are also infrequent in those with an early age of onset or those with multiple primary melanomas.(1) However, the incidence of CDKN2A mutations increases with a positive family history; CDKN2A mutations will be found in 5% of families with firstdegree
relatives, rising to 20% to 40% in kindreds with 3 or more affected first-degree relatives.(2) Mutation detection rates in the CDKN2A gene are generally estimated as 20% to 25% in hereditary CMM 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 mutation are available.(3,4)
Familial CMM has been described as a family in which either 2 first-degree relatives are diagnosed with melanoma or a family with 3 melanoma patients, irrespective of the degree of relationship.(5) Others have defined familial CMM 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.(6) No widely accepted guidelines for the management of families with hereditary risk of melanoma exist.(7)
Other malignancies associated with familial CMM, specifically those associated with CDKN2A mutations, 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 mutations
have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.
CMM can occur either with or without a family history of multiple dysplastic nevi. Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). 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 CMM. Initially, the phenotypes of atypical nevi and CMM were
thought to cosegregate in FAMMM families, leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A mutations, there were family members with multiple atypical nevi who were noncarriers of the CDKN2A familial mutation. Thus, the nevus phenotype cannot be used to distinguish carriers from noncarriers of CMM susceptibility in these families.
Some common allele(s) are associated with increased susceptibility to CMM 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 CMM. This gene is associated with fair complexion, freckles, and red hair, all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A mutations.(8)
Melaris® (Myriad Genetics. Salt Lake City, UT) is a commercially available genetic test of the CDKN2A gene.
No U.S. Food and Drug Administration (FDA)‒approved CDKN2A mutation tests were identified. Melaris® and other CDKN2A tests are laboratory-developed tests (LDTs). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Melaris® is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require any regulatory review of this test.
Genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
Effective in 2013, there is CPT coding to more specifically report CDKN2A testing. Code 81404 includes:
CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence
Prior to 2013, there were no specific CPT codes for genetic testing specifically for susceptibility to malignant melanoma. A series of CPT codes describing the individual steps in the genetic analysis would have been used.
BlueCard/National Account Issues
Genetic testing for mutations associated with malignant melanoma will likely be performed at specialty laboratories.
This policy was originally created in 2005 and has been updated regularly with searches of the MEDLINE database. The most recent literature review was performed for the period through September 8, 2014. Following is a summary of the key literature to date.
Validation of the clinical use of any diagnostic test focuses on 3 main principles: (1) analytic validity of the test; ie, the technical performance of the test; (2) clinical validity, ie, the diagnostic performance of the test, such as sensitivity, specificity, and positive and negative predictive values in different populations of patients and compared with the criterion standard; and (3) clinical utility of the test, ie, how the results of the diagnostic test will be used to improve patient management.
Genetic testing typically comprises sequence analysis of the coding regions and intron/exon splice sites or analysis of a specific mutation. Studies have identified deleterious mutations in the 5untranslated region and deep intronic mutations in the CDKN2A gene.
Clinical validity is related to interpretation of the results of genetic analysis for the individual patient. One issue common to genetic testing for any type of cancer susceptibility is determining the clinical significance of individual mutations. For example, mutations in the CDKN2A gene can occur along its
entire length, and some of these mutations represent harmless polymorphisms or noncoding mutations. Interpretation will improve as more data accumulate regarding the clinical significance of individual mutations in families with a known hereditary pattern of melanoma. However, the penetrance of a given
mutation will also affect its clinical significance, particularly because the penetrance of CDKN2A mutations may vary with ethnicity and geographic location.(1,2) For example, exposure to sun and other environmental factors, as well as behavior and ethnicity may contribute to penetrance. Bishop et al (2002)
estimated that the calculated risk of developing melanoma before age 80 years in carriers of CDKN2A mutations ranged from 58% in Europe to 91% in Australia.(9)
Interpretation of a negative test is another issue. CDKN2A mutations are found in less than half of those with 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.(1) For example, in a 2011 meta-analysis of 145 genome-wide association studies, 8 independent, genetic loci were identified as being associated with a statistically significant risk of cutaneous melanoma, including 6 with strong epidemiologic credibility (MC1R, TYR, TYRP1,
SLC45A2, ASIP/PIGU/MYH7B, CDKN2A/MTAP).(10) Also, in a 2011 meta-analysis of 20 studies with data from 25 populations, red hair color variants on the MC1R gene were associated with the highest risk of melanoma, but non‒red hair color variants also were associated with an increased risk of melanoma.(
11) In a 2012 review, Ward et al noted the genetics of melanoma are far from being understood, and “it is likely a large number of SNPs (single nucleotide polymorphisms), each with a small effect and low penetrance, in addition to the small number of large effect, high-penetrance SNPs, are responsible for CMM (cutaneous malignant melanoma) risk.”(12)
In 2009, Yang et al conducted a study to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations.(13) Investigators genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A-positive, 9 CDKN2A-negative) for genes involved in DNA repair, apoptosis, and immune
response. Their analyses identified some candidate genes, such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9, and JAK3, that were associated with CMM risk; after correction for multiple comparisons, IL9 remained significant. The effects of some genes were stronger in CDKN2A
mutation-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 polymorphisms in DNA repair, apoptosis, and immune response pathways may modify the risk of CMM in CMM-prone
families, with or without CDKN2A mutations.
In 2010, Kanetsky et al conducted a study to describe associations of MC1R (melanocortin 1 receptor gene) variants and melanoma in a U.S. population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure.(14) 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 of high- and low-risk MC1R variants and melanoma, overall and within phenotypic and sun exposure groups. Carriage of 2 low-risk, or any highrisk
MC1R variant was associated with increased risk of melanoma (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0 to 2.8; OR=2.2; 95% CI, 1.5 to 3.0, respectively). However, 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 these findings indicate MC1R genotypes provide information about melanoma risk in those individuals who would not be identified as high risk based on their phenotypes or exposures
alone. However, how this information impacts patient care and clinical outcomes is unknown.
Two subsequent studies in southern European populations examined further the association of MC1R variants and melanoma. Ibarrola-Villava et al (2012) conducted a case control study in 3 sample populations from France, Italy, and Spain.(15) Susceptibility genotypes in 3 genes involved in pigmentation
processes were examined in 1639 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—also were 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: OR for 1 allele: 2.2 (95% CI, 1.9 to 2.6); OR for 2 alleles: 5.0
(95% CI, 2.8 to 8.9). In 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. Effects on health outcomes are unknown.
Ghiorzo et al (2012) studied 49 CDKN2A-mutation positive and 390 CDKN2A-mutation negative Italian patients with cutaneous melanoma.(16) MC1R variants were associated with increased odds of melanoma only in CDKN2A-mutation-negative patients in a dose-dependent fashion: OR for 1 high-risk allele: 1.5
(95% CI, 1.1 to 2.0); OR for 2 high-risk alleles, 2.5 (95% CI, 1.7 to 3.7). In multivariate logistic regression, effects of MC1R variants were statistically significant in most CDKN2A mutation-negative subgroups and few mutation-positive subgroups defined by phenotype (eye and hair color, skin complexion and
phototype, presence or absence of freckles or atypical nevi, and 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 mutation-positive (OR=71.2; 95% CI, 23.0 to 221.0) and mutationnegative (OR=5.3; 95% CI, 2.0 to 14.3) patients, although uncertainty in the estimates of association was considerable. Family history of cutaneous nevi (at least 1 first-degree relative with >10 nevi and /or atypical nevi) increased the odds of melanoma in mutation-positive cases only (OR=2.44; 95% CI, 1.3 to 4.5). This finding underscores the significance of nongenetic factors (eg, sun exposure, and history of severe sunburn) for development of melanoma and the complexity of interpreting a positive family history.
Cust et al (2012) classified 565 patients with invasive cutaneous melanoma diagnosed between 18 to 39 years of age, 518 sibling controls, and 409 unrelated controls into MC1R categories defined by presence of high risk or other alleles.(17) Compared with sibling controls, 2 MC1R high-risk alleles (R151C, R160W) were associated with increased odds of developing melanoma (OR=1.7; 95% CI, 1.1 to 2.6; OR=2.0; 95% CI, 1.2 to 3.2, respectively), 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 adjusted analysis. There was no association between other MC1R alleles (not considered high risk) and odds of developing melanoma in unadjusted or adjusted analyses. In 2010, Psaty et al published an article on identifying individuals at high risk for melanoma and emphasized the use of family history.(18)
In 2013, Puntervoll et al published a description of the phenotype of individuals with CDK4 mutations in 17 melanoma families (209 individuals; 62 cases, 106 related controls, 41 unrelated controls).(19) The incidence of atypical nevi was higher in those with CDK4 mutations (70% in melanoma patients; 75% in
unaffected individuals) than in those without CDK4 mutations (27%; p<0.001). The distribution of eye color or hair color was not statistically different between CDK4 mutation-positive individuals (with or without melanoma) and mutation-negative family members. The authors concluded that “it is not possible
to distinguish CDK4 melanoma families from those with CDKN2A mutation based on phenotype.” As noted previously, the clinical significance of this genetic distinction is currently unclear.
In 200320 and 2010,21 the American Society of Clinical Oncology 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 be offered only 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.
Although genetic testing for CDKN2A mutations is recognized as an important research tool, its clinical use will depend on how results of genetic analysis can be used to improve patient management. Currently, management of patients considered high risk for malignant melanoma focuses on reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. (See Policy No. 2.01.42 for further discussion of dermatoscopy and related techniques for skin surveillance.) Presently, it is unclear how genetic testing for CDKN2A would alter these management recommendations. The following clinical situations can be considered.
1. Affected individual with a positive family history
If an affected individual tests positive for a CDKN2A mutation, he/she 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 a malignant melanoma,
regardless of the presence of a CDKN2A mutation. However, a positive result will establish a mutation, thus permitting targeted testing for the rest of the family. Additionally, a positive mutation in an affected family member increases the likelihood of its clinical significance if detected in another family member. As described earlier, a negative test is not interpretable.
2. Unaffected individual in a high-risk family
If the unaffected individual is the first to be tested in the family (ie, no affected relative has been previously tested to define the target mutation), it is very difficult to interpret the clinical significance of a mutation, as described. The likelihood of clinical significance is increased if the identified mutation is the
same as one reported in other families, although the issue of penetrance is a confounding factor. If the unaffected individual has the same mutation as an affected relative, then the patient is at high risk for melanoma. However, again it is unclear how this would affect the management of the patient. Increased
sun protection and surveillance are recommended for any patient in a high-risk family.
Published data on genetic testing of the CDKN2A and CDK4 genes focus on the underlying genetics of hereditary melanoma, identification of mutations in families at high risk of melanoma, and risk of melanoma in those harboring these mutations. Other studies have focused on the association between
CDKN2A and pancreatic cancer.(22-24) One publication added the caution that differences in melanoma risk across geographic regions justify the need for studies in individual countries before counseling should be considered.(25)
In a 2008 study, Aspinwall et al found short-term change in behavior among a small group of patients without melanoma who were positive for the CDKN2A mutation.(26) In this prospective study of 59 members of a CDKN2A mutation-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 mutation 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 outcomes for 37 patients (62%) of this cohort who were available for 2-year follow-up.(27,28) 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 knowledge of test results.
In a 2011 retrospective case-control study, van der Rhee et al sought to determine whether a surveillance program of families with a Dutch founder mutation in CDKN2A (the p16-Leiden mutation) allowed for earlier identification of melanomas.(29) Characteristics of 40 melanomas identified in 35 unscreened
patients (before heredity was diagnosed) were compared with 226 melanomas identified in 92 relatives of those 35 unscreened melanoma patients who were found to have the CDKN2A mutation and participated in a surveillance program over a 25-year period. Surveillance comprised 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 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 was still observed in the surveillance program, and almost half of patients were noncompliant when first diagnosed with melanoma.
In 2013, van der Rhee et al reported on a retrospective case-control study of 21 families with the p16-Leiden founder mutation.(30) The purpose of the study was to investigate 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 rate was 9.9 per 1000 person-years (95% CI, 7.4 to 13.3) in first-degree relatives and 2.1 per 1000 person-years (95% CI, 1.2 to 3.8) in second-degree relatives. In comparison with the general population in the Netherlands, overall standardized morbidity ratio for melanoma was 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 conclude that surveillance of second- (as well as first-) degree relatives from very high-risk melanoma families is justified based on these findings, it is unclear whether these findings apply to families without or with other CDKN2A mutations. Further, because increased sun protection and surveillance are recommended for any member of a high-risk family, clinical relevance of the finding is
Branstrom et al (2012) examined a survey of self-reported genetic testing perceptions and preventive behaviors in 312 family members with increased risk of melanoma. Fifty-three percent had been diagnosed with melanoma, and 12% had a positive susceptibility genetic test.(31) The study indicated that a
negative test might be associated with an erroneous perception of lower risk and fewer preventive measures.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov using the search terms “melanoma,” “pancreatic cancer,” “genetic,” and “families” identified 5 observational studies, 4 sponsored by the National Cancer Institute and 1 sponsored by the Medical University of Vienna. Four seek to identify genetic and environmental
factors related to melanoma risk in individuals and families at high risk for melanoma (NCT00040352, NCT00450593, NCT00339222, NCT00849407). Another study to develop a model for genetic susceptibility for melanoma is active but no longer recruiting patients (NCT00591500).
Summary of Evidence
Because some cases of cutaneous malignant melanoma (CMM) are familial, potential genetic markers for this disease are being evaluated. Some of these markers are being evaluated in those with a family history of disease; other markers are being evaluated to estimate the risk of CMM in those who may not
have a family history.
Evidence to date is insufficient to permit conclusions concerning the effect of genetic testing on health outcomes. Although research continues in this area, none of the articles demonstrated how the presence or absence of these genetic mutations would impact clinical care—either for those with melanoma or for
those at risk due to a family history of melanoma. Changes in patient management that result from finding a mutation in a patient at risk are unknown. In addition, not finding a mutation does not exclude the presence of familial CMM. The conclusion concerning unknown impact on outcomes applies both to
mutations with high penetrance (CDKN2A) and to those with low penetrance (MC1R) that may increase susceptibility. Therefore, genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered
Practice Guidelines and Position Statements
Melanoma Genetics Consortium
In 2002, Melanoma Genetics Consortium, comprising familial melanoma researchers from North America, Europe, and Australia, indicated that genetic testing for melanoma susceptibility should not be offered outside of a research setting.(32)
American Society of Clinical Oncology
In a 2002 American Society of Clinical Oncology (ASCO) publication, Kefford et al noted that the sensitivity and specificity of tests for CDKN2A mutations are not fully known.(33) Because interpreting genetic tests is difficult and because test results do not alter patient management, the Kefford publication
indicated that CDKN2A genetic testing should be performed only in clinical trials for several reasons including: a low likelihood of finding mutations in known melanoma susceptibility genes, uncertainty about the functionality and phenotypic expression of the trait among mutation 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 2010, ASCO updated its policy statement on genetic and genomic testing for cancer susceptibility.(21) ASCO recommends that “genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials.”
National Comprehensive Cancer Network
Current National Comprehensive Cancer Network clinical practice guidelines for melanoma (version 4.2014) include no specific recommendation for genetic testing for melanoma.(34)
U.S. Preventive Services Task Force Recommendations
No U.S. Preventive Services Task Force recommendations for genetic testing for malignant melanoma have been identified.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Hayward NK. Genetics of melanoma predisposition. Oncogene. May 19 2003;22(20):3053-3062. PMID 12789280
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):3245-3251. PMID 10506626
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):501-506. PMID 16169933
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):552-559. PMID 20068151
de Snoo FA, Bergman W, Gruis NA. Familial melanoma: a complex disorder leading to controversy on DNA testing. Fam Cancer. 2003;2(2):109-116. PMID 14574160
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):137-143. PMID 17055252
Marzuka-Alcala A, Gabree MJ, Tsao H. Melanoma susceptibility genes and risk assessment. Methods Mol Biol. 2014;1102:381-393. PMID 24258989
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):173-179. PMID 16462187
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
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):1227-1235. PMID 21693730
Williams PF, Olsen CM, Hayward NK, et al. Melanocortin 1 receptor and risk of cutaneous melanoma: a metaanalysis and estimates of population burden. Int J Cancer. Oct 1 2011;129(7):1730-1740. PMID 21128237
Ward KA, Lazovich D, Hordinsky MK. Germline melanoma susceptibility and prognostic genes: A review of the literature. J Am Acad Dermatol. May 12 2012. PMID 22583682
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):2912-2917. PMID 19626699
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):2416-2428. PMID 20301115
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):2183-2191. PMID 22464347
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):718-720. PMID 22804906
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 1 2012;131(3):E269-281. PMID 22095472
Psaty EL, Scope A, Halpern AC, et al. Defining the patient at high risk for melanoma. Int J Dermatol. Apr 2010;49(4):362-376. PMID 20465687
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):264-270. PMID 23384855
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. Jun 15 2003;21(12):2397-2406. PMID 12692171
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. February 10, 2010 2010;28(5):893-901. PMID 20065170
Puig S, Malvehy J, Badenas C, et al. Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol. May 1 2005;23(13):3043-3051. PMID 15860862
Rulyak SJ, Brentnall TA, Lynch HT, et al. Characterization of the neoplastic phenotype in the familial atypical multiple-mole melanoma-pancreatic carcinoma syndrome. Cancer. Aug 15 2003;98(4):798-804. PMID 12910525
Rutter JL, Bromley CM, Goldstein AM, et al. Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study. Cancer. Dec 15 2004;101(12):2809-2816. PMID 15529312
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):825-831. PMID 17397031
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):1510-1519. PMID 18559569
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):276-289. PMID 23382133
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):1687-1697. PMID 23950214
van der Rhee JI, de Snoo FA, Vasen HF, et al. Effectiveness and causes for failure of surveillance of CDKN2Amutated melanoma families. J Am Acad Dermatol. Aug 2011;65(2):289-296. PMID 21570154
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):1771-1777. PMID 23897584
Branstrom 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. Jun 20 2012. PMID 22726816
Kefford R, Bishop JN, Tucker M, et al. Genetic testing for melanoma. Lancet Oncol. Nov 2002;3(11):653-654. PMID 12424065
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.
National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: melanoma, version 4.2014. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed August 8, 2014.
|CPT||See Policy Guidelines|
|ICD-9 Diagnosis||Investigational for all relevant codes|
|ICD-10-CM (effective 10/1/15)||Investigational for all relevant diagnoses|
|Z12.83||Encounter for screening for malignant neoplasm of skin|
|Z80.8||Family history of malignant neoplasm of other organs or systems (includes melanoma)|
|ICD-10-PCS (effective 10/1/15)||Not applicable. No ICD procedure codes for laboratory tests|
Genetic Testing, Melanoma
Melanoma, Genetic Testing
|09/27/05||Add policy to Medicine section, Pathology Laboratory subsection||New policy|
|06/14/07||Replace Policy||Policy updated with literature search through April 2007; remains investigational. Description expanded with more information about familial melanoma, familial atypical multiple mole and melanoma (FAMMM), and hereditary risk for melanoma vs. increased susceptibility. Title and policy statement modified to deal with both hereditary melanoma and increased susceptibility. Reference numbers 3 to 5 and 11 added.|
|08/14/08||Replace policy||Policy updated with literature search; reference number 12 added. Policy statement unchanged.|
|09/16/10||Replace policy||Policy updated with literature search, reference numbers 13-15 added. Policy statement unchanged|
|9/01/11||Replace policy||Policy updated with literature search through July 2011, reference numbers 12 and 16 added. “Familial” added to the policy title and replaced hereditary in the policy statement and throughout the policy.|
|9/13/12||Replace policy||Policy updated with literature search through July 2012, reference numbers 7-8 and 19 added. Policy statement unchanged|
|11/8/12||Replace policy- coding update only||CPT coding updated|
|10/10/13||Replace policy||Policy updated with literature search through August 2013; references 12-14, 16, and 26 added; reference 25 updated. Policy statement unchanged.|
|10/09/14||Replace policy||Policy updated with literature review through September 8, 2014; references 3-4, 7, 20, 27-28, and 30 added; reference 34 updated. Policy statement unchanged.|