Correspondence

The Atypical-Mole Syndrome and Predisposition to Melanoma

N Engl J Med 1998; 339:348-349July 30, 1998

Article

To the Editor:

Abnormal melanocytic nevi are a potent risk factor for sporadic melanoma. In persons with a family history of melanoma, the presence of this phenotype is commonly used to identify candidates for screening and surveillance because their risk of melanoma is believed to be increased. We carried out genotype and phenotype studies in families with germ-line CDKN2 mutations and found that the correlation between having the abnormal-nevus phenotype and actually carrying the mutant gene is so poor that this approach to screening is not tenable.

Clark et al. described two families at increased risk for melanoma1 in which the atypical-mole syndrome phenotype appeared to be associated with the risk of melanoma. Subsequently, they suggested that in these genetically predisposed families, the nevi were both markers of risk and precursors of melanoma. There have been other reports of families at increased risk for melanoma with the atypical-mole syndrome,2,3 although there have also been rarer reports of such families without the syndrome.

Members of five families with causal germ-line mutations in the CDKN2 gene4 were examined by dermatologists who were unaware of the subjects' carrier status. The atypical-mole syndrome score (range of possible values, 0 to 5) was determined according to a published definition5 that is based on a five-point checklist: the total number of nevi, the presence of two or more clinically atypical nevi, and three measures of abnormally distributed nevi. Subjects with a score of 3 or more were classified as having the atypical-mole syndrome phenotype.

Although many subjects had the atypical-mole syndrome, there was variation within families and between families. We compared nevi in carriers and noncarriers using the Wilcoxon rank-sum test and analysis of variance. Gene carriers had a larger total number of nevi (P= 0.003), even after adjustment for differences between families, and a tendency toward having more atypical nevi (P=0.07).

The atypical-mole syndrome score also correlated with carrier status (P=0.02), but there was a large degree of overlap between those with the mutant gene and those without it (Table 1Table 1Characteristics of Nevi, Carrier Status with Respect to the CDKN2 Gene, and Atypical-Mole Syndrome Score in Five Families with a History of Germ-Line Mutations in CDKN2.). The correlation was so poor within families that we believe that the clinical practice of using the atypical-mole syndrome phenotype to identify candidates for surveillance is inappropriate. Germ-line mutations of the CDKN2 gene are found in 30 to 40 percent of melanoma-prone families (those with three or more members with melanoma). On the basis of available data, we believe that it is prudent to consider all members of such families as potential carriers who are at increased risk for melanoma.

Rachel C. Wachsmuth, M.B., M.R.C.P.
Mark Harland, Ph.D.
Julia A. Newton Bishop, M.D., F.R.C.P.
St. James's University Hospital, Leeds LS9 7TF, United Kingdom

5 References

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Citing Articles (12)

Citing Articles

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   A. Buendía-Eisman, M.C. Paláu-Lázaro, S. Arias-Santiago, A. Cabrera-León, S. Serrano-Ortega. (2011) Prevalence of melanocytic nevi in 8- to 10-year-old children in Southern Spain and analysis of associated factors. Journal of the European Academy of Dermatology and Venereologyno-no
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   Sancy A. Leachman, John Carucci, Wendy Kohlmann, Kimberly C. Banks, Maryam M. Asgari, Wilma Bergman, Giovanna Bianchi-Scarrà, Teresa Brentnall, Brigitte Bressac-de Paillerets, William Bruno, Clara Curiel-Lewandrowski, Femke A. de Snoo, Tadeusz Debniak, Marie-France Demierre, David Elder, Alisa M. Goldstein, Jane Grant-Kels, Allan C. Halpern, Christian Ingvar, Richard F. Kefford, Julie Lang, Rona M. MacKie, Graham J. Mann, Kurt Mueller, Julia Newton-Bishop, Håkan Olsson, Gloria M. Petersen, Susana Puig, Darrell Rigel, Susan M. Swetter, Margaret A. Tucker, Emanuel Yakobson, John A. Zitelli, Hensin Tsao. (2009) Selection criteria for genetic assessment of patients with familial melanoma. Journal of the American Academy of Dermatology 61:4, 677.e1-677.e14
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   Véronique Winnepenninckx, Joost J van den Oord. (2007) Gene expression profiling and clinical outcome in melanoma: in search of novel prognostic factors. Expert Review of Anticancer Therapy 7:11, 1611-1631
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   Lana Pho, Douglas Grossman, Sancy A Leachman. (2006) Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Current Opinion in Oncology 18:2, 173-179
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   Eduardo Nagore, Alegr??a Montoro, Silvestre Oltra, Eduardo Ledesma, Rafael Botella-Estrada, Jos?? M. Mill??n, Vicente Oliver, Jos?? M. Fortea, Carlos Guill??n. (2005) Age does not appear to be a major indicator of CDKN2A or CDK4 mutations in melanoma patients in Spain. Melanoma Research 15:6, 555-558
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   Mandi Sachdeva, Gwyn E. Frambach, A. Neil Crowson, April C. Deng, Martin C. Mihm, Cynthia M. Magro. (2005) De novo intraepidermal epithelioid melanocytic dysplasia as a marker of the atypical mole phenotype - a clinical and pathological study of 75 patients. Journal of Cutaneous Pathology 32:9, 622-628
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   V. Chaudru, A. Chompret, B. Bressac-de Paillerets, A. Spatz, M.-F. Avril, F. Demenais. (2004) Influence of Genes, Nevi, and Sun Sensitivity on Melanoma Risk in a Family Sample Unselected by Family History and in Melanoma-Prone Families. JNCI Journal of the National Cancer Institute 96:10, 785-795
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   Brigitte Bressac-de-Paillerets, Marie-Françoise Avril, Agnès Chompret, Florence Demenais. (2002) Genetic and environmental factors in cutaneous malignant melanoma. Biochimie 84:1, 67-74
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   Lucia Pozo, MD, Alfredo Blanes, MD, Salvador J. Diaz-Cano, MD, Rino Cerio, MD, Mahmoud Naase, PhD. (2001) Critical Analysis of Histologic Criteria for Grading Atypical (Dysplastic) Melanocytic Nevi. American Journal of Clinical Pathology 115:2, 194-204
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    Nicholas Hayward. (2000) New developments in melanoma genetics. Current Oncology Reports 2:4, 300-306
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    Michael Piepkorn. (2000) Melanoma genetics: An update with focus on the CDKN2A(p16)/ARF tumor suppressors. Journal of the American Academy of Dermatology 42:5, 705-726
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    M.J Hicks, C.M Flaitz. (2000) Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncology 36:2, 152-169
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