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© 1999 American Society for Clinical Oncology Counseling and DNA Testing for Individuals Perceived to Be Genetically Predisposed to Melanoma: A Consensus Statement of the Melanoma Genetics ConsortiumFrom the Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, New South Wales, Australia; Imperial Cancer Research Fund (ICRF) Cancer Medicine Research Unit and ICRF Genetic Epidemiology, St James's University Hospital, Leeds, United Kingdom; Leiden University Medical Centre, Leiden, the Netherlands; and National Cancer Institute, Rockville, MD. Address reprint requests to Richard Kefford, MD, Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, New South Wales 2130, Australia; email kefford{at}westgate.wh.usyd.edu.au
THIS DOCUMENT represents the consensus view of the Melanoma Genetics Consortium on appropriate responses to requests for genetic counseling of persons perceived to be at high risk of cutaneous melanoma. The major determinant of interest in genetic testing is a positive family history of melanoma with multiple affected relatives, as members of melanoma-prone families are at substantially increased risk of melanoma.1 This document is therefore concerned primarily with advice given to high-risk families and with recommended programs of surveillance and primary prevention for them. These same surveillance and prevention programs may, however, be justified in others deemed to be at high risk of developing melanoma for any of the other known risk factors listed in Table 1. The best currently available estimates of risk have been used.
The proportion of all cutaneous melanomas that is attributable to the inheritance of autosomal dominantly inherited mutations in melanoma susceptibility genes is unknown, but it is estimated by the Consortium to be less than 1% to 2%. This is the approximate proportion of melanoma cases involving multiple relatives also affected by melanoma. More frequently, a person newly diagnosed with melanoma will report one other relative with melanoma (Table 1). Such families may or may not have the same level of risk as families with many members with melanoma, and careful verification of their family history is a cornerstone of their risk assessment. Families in which these genes are inherited have members who may be distinguished by the presence of some, but not necessarily all, of the features listed in Table 2. Of particular interest is that in certain, but not all, of these families, there seems to be an association with the presence of multiple unusual or atypical moles.
Constitutional mutations in two genes, CDKN2A and CDK4, have so far been found to confer risk in melanoma families, although it is highly likely that there are others yet to be identified.
The CDKN2A locus on human chromosome region 9p21 encodes two distinct proteins translated, in alternate reading frames (ARFs), from alternatively spliced transcripts. The alpha transcript, comprising exons 1
• Two families in the United States and one in France have mutations in the CDK4 gene on chromosome 12q which inhibit binding of its inhibitor, p16INK4A.14,15 • The genetic basis for the remaining 60% to 80% of families, in which highly penetrant genes may be operating, is the subject of active research by the Melanoma Genetics Consortium. New families are keenly sought and may be reported to members of the Melanoma Genetics Consortium in the country of greatest convenience for referring clinicians. The Appendix gives a full list of current Consortium members. • Mutations in the CDKN2A gene occur throughout the first two of the three exons,16 and a mutation in the 5'-untranslated region has also been described.17 • Because current information on each mutation is limited and confined to data from large, specifically ascertained families, the confidence limits on current estimates of penetrance of mutations in the CDKN2A gene are extremely wide. Assessment of penetrance is also the subject of intense interest for the Consortium. • This penetrance seems to be strongly influenced by birth cohort,18 levels of sun exposure,19,20 and possibly by modifier genes, which, in certain families, may also be responsible for the presence of multiple moles.20
Characteristics of familial melanoma among high-risk families include frequent multiple primary melanomas, early age of onset of first melanoma, and frequently the presence of atypical or dysplastic nevi (moles) (Table 2). Neither these nor any other characteristics are good clinical predictors of the likelihood of carrying a mutation in a melanoma susceptibility gene. The best predictor at present is having melanoma with a strong family history of melanoma. Even among these high-risk families, less than half will have CDKN2A mutations (Table 2).
Among patients with multiple primary melanomas without regard to family history, a small percentage may be found to have mutations in CDKN2A (Table 2). Genetic testing for mutations among individuals with multiple primary melanomas alone is still a research question; it is not recommended as part of routine care at this time. In a similar manner, early age of onset of melanoma is common in high-risk families, but in a clinical setting, genetic testing for CDKN2A mutations is currently a research tool only. Atypical or dysplastic nevi are major risk factors for melanoma, both in high-risk families and in the general population.9,21 The relationship between these nevi and melanoma susceptibility genes is unclear at present. Although early on, dysplastic nevi and melanoma were proposed to be pleiotropic effects of a single gene,22 more recent data suggest that these nevi are independent risk factors for melanoma.20 In addition to families in which the predominant cancer is melanoma, there are other rare families in which melanoma is part of the constellation of observed cancers. Cutaneous melanoma is among the most common second cancers in individuals with heritable retinoblastoma.23 Cutaneous melanoma occasionally occurs in families with Li-Fraumeni syndrome, some of which have germline mutations in TP53.24 Cutaneous melanoma is also increased in two autosomal recessive conditions, xeroderma pigmentosa25,26 and Werner's syndrome (adult progeria).27,28
There is a demand for gene testing from some families with an inherited pattern of melanoma and concern on the part of clinicians about the role of that testing. The demand for gene testing from families is frequently based on an unrealistic expectation of its definitiveness, sensitivity, and specificity. Given the current paucity of knowledge about the penetrance of CDKN2A mutations, the failure as yet to identify mutations in over 60% of hereditary melanoma kindreds, and the limited data on the efficacy of prevention and surveillance strategies,21 the most prudent clinical course is to enroll all members of high-risk kindreds in the same common-sense programs of surveillance and prevention, irrespective of their DNA status. The Melanoma Genetics Consortium recommends, therefore, that DNA testing for mutations in known melanoma susceptibility genes should only rarely be performed outside of defined research programs. With this general proviso, two distinct clinical situations need further consideration: families in which a CDKN2A mutation has been identified in a proband as part of a research study and families for which no prior testing of affected individuals has been conducted.
Families in Which a CDKN2A Mutation Has Been Identified in a Proband as Part of a Research Study Some CDKN2A mutations have been identified in families around the world and have been shown to co-segregate with tumors in the family. Moreover, for a proportion, in vitro functional tests have shown evidence that the mutation is likely to be causal, as the mutant p16INK4A proteins were impaired in their ability to inhibit the catalytic activity of the target cyclin D1/CDK4 and cyclin D1/CDK6 complexes.33 It is reasonable to offer genetic counseling and education about melanoma prevention strategies to such families. Even for these families, there is little information about penetrance. In other families, novel putative mutations have been identified for which no functional data are available. Some of these mutations are likely to be population polymorphisms of no functional significance. The Consortium's view is that genetic counseling about these mutations is currently premature. The pretest education and counseling should include information about the following:
• the lack of proved efficacy of prevention and surveillance strategies based on DNA testing, even for mutation carriers; • the fact that a negative test result at best returns risk to that of the general population, which in certain localities may be as high as one in 25 people. Prevention and surveillance strategies must, therefore, continue in this group. Within the families identified so far, in which a CDKN2A mutation has been identified, there is a lack of correlation between the presence of the atypical or dysplastic moles and gene carrier status,20,32,34 which has led to the suggestion that within these families, other genes may induce moles and may increase risk of melanoma. Recent data suggest that atypical or dysplastic moles confer a risk of melanoma in family members independent of CDKN2A mutation status20; • and the potential benefits and risks of positive and negative results of genetic testing (Table 3).
When a mutation in CDKN2A has been found in affected members of a family, the sensitivity of genetic testing is not an issue, because results of a simple allele-specific oligonucleotide test, specific for the mutation already identified in the family, will be positive in all mutation carriers. However, the penetrance of such mutations remains so uncertain as to make accurate risk assessment extremely difficult for the genetic counselor. Not all mutations have been demonstrated to cause a functional deficit, and confusion with polymorphisms may potentially occur. Furthermore, melanomas have occurred in non–gene carriers in CDKN2A mutation–carrying kindreds,32 and some gene carriers living to older ages have not developed melanoma.35 This further highlights the importance of recommending surveillance and prevention for all members of these families, irrespective of their DNA status, especially in countries such as Australia that have high population rates for the tumor. An advantage of testing for certain individuals may be a subjective, psychologic one, poorly studied at present but anecdotally reported as a perception of freedom of parent guilt for those who test negative. These individuals report a sense of relief that they have not transmitted the disease-associated gene to their offspring. This potential "benefit" of testing must be weighed against the potential for survivor guilt, well described in those who test carrier-negative for other inherited diseases.36
Families for Which No Prior Testing of Affected Individuals Has Been Conducted Table 4 gives an estimate of the frequency with which CDKN2A mutations will be found by genomic sequencing in individuals of different categories; these estimates may be useful in assisting this discussion. Because there are few population-based data on which to base these estimates,16 they must be considered as guides only and almost undoubtedly as overestimates.
The potential benefits and risks associated with genetic testing for melanoma are similar to those for the testing of other cancer susceptibility genes and are summarized in Table 3.
Given current gaps in knowledge about the expression of melanoma susceptibility genes in the population, DNA testing cannot be used as a guide to the clinical practice of prevention and surveillance. All individuals deemed to be at high risk of melanoma, because of the presence of any of the risk factors outlined in Table 1, should be managed with the same attention to the following measures, as previously outlined by others for those at high-risk of melanoma.38,39 In the absence of randomized, controlled, clinical trial–based data, the evidence for each of these measures is level IV. Education of all family members about the need for sun protection is essential. Parents in particular should be educated about sun protective measures for infants and children,38,40,41 including the use of sun-protective clothing, the use of hats and sunglasses, the use of broad-spectrum ultraviolet A and ultraviolet B protective sunscreens,42,43 avoidance of peak ultraviolet conditions, and absolute avoidance of sunburns. Commencing at the age of 10 years, family members should have a baseline skin examination with characterization of moles. Overview photographs of the entire skin surface and close-up photographs of atypical nevi are useful. Individuals should be taught about routine self-examination in the hope that this will prompt earlier diagnosis and removal of melanomas. Patients may be given their own copy of photographs and shown how to use these in self-examination. The significance of change in shape and size of pigmented lesions should be understood, and the rules regarding asymmetry, border, color, and diameter (ie, the ABCD rules) are often helpful in this regard.44 Color photographs of early melanomas and atypical moles may be given to the patient as an aid. It is recommended that an appropriately trained health care provider carry out skin examinations every 6 months until the nevi are stable and the patient is judged competent in self-surveillance. Subsequently, the individual should be seen annually or have prompt access to that health care provider as necessary. During puberty or pregnancy, when the nevi may be unstable, more frequent health care provider examinations may be indicated. Examination should include adequate examination of the scalp and genitalia. Skin-surface microscopy (epiluminescence microscopy)45,46 may be helpful in a surveillance program. The indication for surgical removal of a pigmented lesion is the same as in the general population, that is, suspicion of malignant change. There is no justification for prophylactic excision of moles, since the probability of a single nevus becoming melanoma is low and, with time, many nevi will mature and disappear. Furthermore, melanomas may occur on previously entirely normal skin,47 so that "prophylactic" excision of all moles would not change guidelines on surveillance by the patient or the health care provider. The Consortium recommends a monthly self-examination or examination by parent, partner, or family member. A careful initial extended family history is imperative, including the ages and verified histologic diagnoses of all family members with cancer. The pedigree should be revised annually. Screening and surveillance guidelines for other cancers should be carried out as in the general population, with the following special considerations:
2. Melanoma in the context of a presence of a family history (two or more family members) with pancreatic cancer. Certain hereditary melanoma families that carry CDKN2A mutations have an increased incidence of pancreatic adenocarcinoma.1,48 Even within this minority of families, the occurrence of pancreatic cancer is a rare event. At present, there is no reliable screening method for early operable pancreatic carcinoma, and survival is poor even with optimal treatment of early disease.49 At-risk individuals in this subset of families could be a potentially informative group for evaluating the efficacy of endoscopic ultrasound50 or positron emission tomography scanning51 as screening tools for detecting early-stage pancreatic cancer. This, however, is a research question and should not be considered as a standard of care. 3. Where cases of ocular melanoma have occurred in the family, annual fundoscopy after adequate mydriasis is recommended, although it is of unproved efficacy in screening or early detection. The risk in any individual of developing this tumor is likely to be low. The discovery of mutations in the melanoma susceptibility genes CDKN2A and CDK4 in families showing an inherited pattern of cutaneous melanoma has raised expectations in health professionals and patients about the possible value of genetic testing for this disease. The American Society for Clinical Oncology's statement on genetic testing for cancer susceptibility recommends that this testing be performed only when "the test can be adequately interpreted; and the results will influence the medical management of the patient or family member."52 The Melanoma Genetics Consortium, having reviewed current information about these mutations, concludes that neither of these criteria is met for the testing of known melanoma susceptibility genes. It is therefore premature to offer DNA testing outside of defined research protocols, except in rare circumstances and only after careful genetic counseling that adequately addresses the following issues: the low likelihood of finding mutations; current uncertainties about the penetrance of mutations, even if found; the lack of proved efficacy of prevention and surveillance strategies, even for mutation carriers; and the potential benefits and risks of positive and negative results of genetic testing. The Consortium will review this advice regularly, in keeping with developments in the field, to maintain a current consensus opinion.
We thank Jack F. Kefford for editorial advice.
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Tucker MA, Halpern A, Holly EA, et al: Clinically recognized dysplastic nevi: A central risk factor for cutaneous melanoma. JAMA277:1439-1444, 1997 10. Zhang Y, Xiong Y, Yarbrough WG: ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell92:725-734, 1998[Medline] 11. Pomerantz J, Schreiber-Agus N, Liegeois NJ, et al: The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell92:713-723, 1998[Medline] 12. Kamijo T, Zindy F, Roussel MF, et al: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell91:649-659, 1997[Medline]
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Soufir N, Avril MF, Chompret A, et al: Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. Hum Mol Genet7:209-16, 1998 16. Hayward NK: The current situation with regard to human melanoma and genetic inferences. Curr Opin Oncol8:136-142, 1996[Medline] 17. Liu L, Dilworth D, Gao L, et al: Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet21:128-132, 1999[Medline] 18. Battistutta D, Palmer J, Walters M, et al: Incidence of familial melanoma and MLM2 gene. Lancet344:1607-1608, 1994[Medline]
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Goldstein AM, Falk RT, Fraser MC, et al: Sun-related risk factors in melanoma-prone families with CDKN2A mutations. J Natl Cancer Inst90:709-711, 1998 21. Tucker MA, Fraser MC, Goldstein AM, et al: The risk of melanoma and other cancers in melanoma-prone families. J Invest Dermatol 100:350S-355S, 1993 22. Bale SJ, Chakravarti A, Greene MH: Cutaneous malignant melanoma and familial dysplastic nevi: Evidence for autosomal dominance and pleiotropy. Am J Hum Genet38:188-196, 1986[Medline] 23. Moll AC, Imhof SM, Bouter LM, et al: Second primary tumors in patients with retinoblastoma: A review of the literature. Ophthalmic Genet18:27-34, 1997[Medline] 24. Eeles RA: Germline mutations in the TP53 gene. Cancer Surv25:101-124, 1995[Medline] 25. Elder DE: Human melanocytic neoplasms and their etiologic relationship with sunlight. J Invest Dermatol 92:297S-303S, 1989 26. English JS, Swerdlow AJ: The risk of malignant melanoma, internal malignancy and mortality in xeroderma pigmentosum patients. Br J Dermatol117:457-461, 1987[Medline] 27. Goto M, Miller RW, Ishikawa Y, et al: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev5:239-246, 1996[Abstract] 28. Barnett JH, Lee FG, Rinsky MJ: Acral lentiginous melanoma and lentigo maligna occurring in Werner's syndrome. Cutis 32:277-279, 283, 1983
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Goldstein AM, Fraser MC, Clark WH Jr, et al: Age at diagnosis and transmission of invasive melanoma in 23 families with cutaneous malignant melanoma/dysplastic nevi. J Natl Cancer Inst86:1385-1390, 1994 31. Salmon JA, Rivers JK, Donald JA, et al: Clinical aspects of hereditary melanoma in Australia. Cytogenet Cell Genet59:170-172, 1992[Medline] 32. Gruis NA, Sandkuijl LA, van der Velden PA, et al: CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families. Melanoma Res5:169-177, 1995[Medline] 33. Ranade K, Hussussian CJ, Sirkosi RS, et al: Mutations associated with familial melanoma impair p16INK4 function. Nat Genet10:114-116, 1995[Medline]
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Wachsmuth RC, Harland M, Bishop JA: The atypical-mole syndrome and predisposition to melanoma. N Engl J Med339:348-349, 1998 (letter) 35. Holland EA, Beaton SC, Becker TM, et al: Analysis of the p16 gene, CDKN2, in 17 Australian melanoma kindreds. Oncogene11:2289-2294, 1995[Medline] 36. Tibben A, Vegter-van der Vlis M, Skraastad MI, et al: DNA-testing for Huntington's disease in the Netherlands: A retrospective study on psychosocial effects. Am J Med Genet44:94-99, 1992[Medline] 37. Holland EA, Schmid H, Kefford RF, et al: CDKN2A (p16INK4a) and CDK4 mutation analysis in 131 Australian melanoma probands: Effect of family history and multiple primary melanomas. Genes Chromosom Cancer25:1-10, 1999[Medline] 38. National Institutes of Health Consensus Development Conference Statement on Diagnosis and Treatment of Early Melanoma, January 27-29, 1992. Am J Dermatopathol 15:34-43, discussion 46-51, 1993 39. Slade J, Marghoob AA, Salopek TG, et al: Atypical mole syndrome: Risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol32:479-494, 1995[Medline] 40. Ferrini RL, Perlman M, Hill L: American College of Preventive Medicine practice policy statement: Skin protection from ultraviolet light exposure—The American College of Preventive Medicine. Am J Prev Med14:83-86, 1998[Medline] 41. Gasparro FP, Mitchnick M, Nash JF: A review of sunscreen safety and efficacy. Photochem Photobiol68:243-256, 1998[Medline]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
MELANOMA SUSCEPTIBILITY GENES
, 2, and 3, encodes the p16INK4A cyclin-dependent kinase inhibitor, and the smaller beta transcript (exons 1ß, 2, and 3) specifies the alternative product, p14ARF. These CDKN2A encoded proteins play a central role in maintaining cell-cycle control; p16INK4A regulates G1-phase exit by inhibiting the CDK4-mediated phosphorylation of the retinoblastoma protein. p14ARF acts via the p53 pathway to induce cell-cycle arrest or apoptosis in response to hyperproliferative oncogenic signals.
