Phenotypic Variation in Familial Melanoma: Title and subTitle BreakConsequences for Predictive DNA Testing

In this issue of the ARCHIVES, Figl and colleagues¹ from Heidelberg, Germany, report a family in which the proband had multiple primary melanomas as well as her mother's sister. During the course of the investigation, the proband's sister was also diagnosed as having melanoma in situ. This familial predisposition is indicative of familial atypical multiple mole melanoma (FAMMM) syndrome, for which the clinical criteria are 2 first-degree relatives with melanoma or 2 cases (even if more distant relatives) if 1 or both have had multiple primary melanomas or 3 or more cases on the same side of the family. The presence of atypical moles is thus irrelevant in respect of the definition of FAMMM, although in most families, individuals with characteristic nevus phenotypes are present.

Out of scientific interest, gene investigations were carried out in the German family. Surprisingly, the proband, her mother, sister, and her mother's sister appeared to be carriers of a specific 19–base pair deletion in the CDKN2A gene, known as the p16-Leiden mutation, a founder mutation from the Netherlands and outside the Netherlands that is predominantly found in families from Dutch ancestry. In the family described by Figl et al,¹ no Dutch ancestor could be elicited. To investigate whether the mutation in the German family can be considered a de novo mutation, the mutation-bearing haplotype could be compared with the founder haplotype in Dutch families.

An important observation in this German family is the extremely variable phenotype of the gene carriers, varying between multiple primary melanomas as well as other cancer types, 1 melanoma in situ, and no melanoma or other cancer. No information on the presence of atypical moles was reported.

Two other cancers mentioned in the report by Figl et al¹ are Hodgkin lymphoma and ovarian cancer, both of which are not specifically associated with p16-Leiden mutations. In p16-Leiden gene carriers, pancreatic carcinoma is considered a key component of the phenotype with a lifetime risk of 15% to 20%.^{2 - 3} This association is so strong that the gene carrier status of the proband's granduncle within the report is anticipated. Other significant increases in cancer risk associated with the p16-Leiden deletion are risks for cancers of the lip, oral cavity and pharynx, nonmelanoma skin cancer, soft-tissue tumors, and tumors of the brain.³ The occurrence of Hodgkin lymphoma in the article by Figl et al¹ might have been unrelated to the p16-Leiden mutation because no loss of heterozygosity could be demonstrated in tumor tissue. The occurrence of ovarian cancer and breast cancer in this family also warrants checking for BRCA2 mutations, since in rare families, 2 cancer-associated gene mutations can occur.

With regard to the BRAF gene that has been tested in this family, we now know that this gene is definitely not involved in familial cancer; it is considered to be an early mutational event in the development of sporadic melanoma.^{4 - 5}

In the reported family, besides the major melanoma-associated germ-line mutation, several other risk factors seem to play a role. Variants of melanocortin-1 receptor (MC1R) gene are considered to modify melanoma risk in CDKN2A mutation carriers,^{6 - 7} and in the patients described by the Heidelberg group, risky MC1R variants were also found: R151C and R160W were carried by the proband, and her aunt carried the R151C variant. Both lesser affected p16 mutation carriers did not carry risky MC1R variants.

In addition, the proband's polychemotherapy (for Hodgkin lymphoma) can be considered a risk factor for subsequent cancer development and therefore could have influenced the expression of the genotype, as Figl and colleagues¹ considered. Altogether, several factors may have contributed to the clinical outcome in these patients, such as germ-line mutations, low-penetrance susceptibility genes, cancer treatment, and chance (eg, the lymphoma).

Phenotypic variation has been an important issue in FAMMM syndrome since 1980. This has been the main reason why it took until 1994 before the first melanoma susceptibility gene was identified on chromosome 9p21: the CDKN2A gene coding for a cell cycle–regulating protein called p16.^{8 - 9}

In families affected with the p16-Leiden mutation and in many other FAMMM families, phenotypic variation has been reported.¹⁰ Variations relate to melanoma risk, age at onset, occurrence of multiple melanomas, diversity of other cancers, association with pancreatic cancer, and, last but not least, the presence and, more specifically, the number of atypical moles.

Phenotypic variation and the influence of low penetrance genes, as illustrated in the article by Figl and colleagues,¹ are part of the International Melanoma Genetics Consortium's argument that testing healthy family members is premature. Predictive DNA testing allows for the identification of individuals at the highest risk for melanoma. This will ultimately lead to improved prevention and earlier detection. Besides the clinical advantages that predictive testing offers, the result may offer psychological security. Those who turn out to be noncarriers are relieved of the high risk and burden of possible transmission to offspring. On the other hand, predictive DNA testing psychologically can be a burden to people. A DNA test result not only affects just 1 person but also has implications for closely related family members. Those who test negative can even experience survivor guilt: a feeling of guilt toward their mutation-carrying family members instead of relief.^{11 - 12}

However, predictive DNA testing should only be offered when the precise implications of a positive test result are known, accurate information about cancer risks is available, and preventive measures are available to reduce the risks. The offering of predictive DNA testing to melanoma-prone families has therefore become the subject of debate shortly after the identification of the first melanoma susceptibility gene.¹³ The hesitations concerning predictive DNA testing have been published by the International Melanoma Genetics Consortium.¹⁴ Most importantly, risk estimates for mutation carriers are still not well established or have broad confidence intervals. In particular the risk for other cancers, such as pancreatic cancer, a cancer with an extremely high mortality rate for which no preventive measures are known, is not clearly defined. Since not all CDKN2A mutations are associated with pancreatic cancer, risk predictions are hardly possible. Moreover the mutation detection rate in melanoma families is low (approximately 40% in ≥3 melanoma families that are linked to chromosome 9), and therefore many families cannot be offered counseling.

Information on genetic testing for physicians and patients can be found on the International Melanoma Genetics Consortium Web site (http://www.genomel.org).

At the pigmented lesions clinic in Leiden, the Netherlands, we are dealing with a large founder population of p16-Leiden positive families and were able to obtain cancer risk figures that were considered sufficiently reliable to start offering predictive DNA testing.

In doing so, we encountered yet another problem: melanoma risk in nonmutation carriers appears to be increased also. This might be due to as yet unidentified low-penetrance genes (such as nevogenic genes) running in the family.¹⁵ Therefore, increasing knowledge on the underlying mechanisms for melanoma not only has provided answers but also has raised many new questions in respect to the clinical management of melanoma families, as the report by our colleagues from Heidelberg illustrates.

Correspondence: Dr Bergman, Department of Dermatology, B1-92, Leiden University Medical Center, 2300 RC Leiden, the Netherlands (wbergman@lumc.nl).

Financial Disclosure: None reported.