According to Huerta et al., sporadic melanoma is diagnosed at a median age of 57 years, whereas FM patients present up to two decades earlier: Those who are carrying mutations of the CDKN2A gene are diagnosed at a median age of 37 years and the remainder of familial cases is recognized at a median age of 46 years [1]. Similar data have been reported elsewhere [2].

Individuals with increased susceptibility to melanoma are often found to carry multiple atypical nevi [1] [3]. Atypical nevi are characterized by asymmetry, irregular borders, variable pigmentation, and diameters > 6mm [4], whereby irregularity of color has been described to be less pronounced than in melanoma. Since it's these lesions that may eventually transform into skin cancer, FM patients are at higher risks of developing multiple melanomas [1] [3].

Otherwise, the clinical and histopathological features of FM are similar to those of sporadic melanoma [4].

FM is defined as the occurrence of melanoma in two first-degree relatives, or three or more melanoma patients on the same side of the family [5]. In line with the former, the family history of skin cancer is the basis of FM diagnosis. The presence of other types of tumors known to be part of mixed cancer syndromes may also be taken into account. Genetic studies should be carried out to corroborate the diagnosis of FM and to lay the foundation for the familial workup. Unfortunately though, genetic analyses yield inconclusive results in more than half of the affected families, so the identification of the underlying mutation(s) is not currently a precondition for the diagnosis of FM. Beyond the familial workup, the molecular biological characterization of the individual tumor may be helpful to estimate its susceptibility to specific molecular-targeted therapies.

Melanoma diagnosis in FM patients does not differ from non-familial cases. The entire skin should be assessed for suspicious lesions and the patient should be queried as to possible changes in the appearance of moles. Virtually all melanomas evolve. If doubts arise regarding a specific lesion, it may be examined with a dermoscope. Surface pattern analysis and history of change allow for a fairly accurate identification of melanoma, but biopsy specimens should be obtained and microscopically examined to confirm the diagnosis [4].

Little is known about possible differences in the histological features of familial and sporadic melanoma or the distinct types of FM. Huerta and colleagues reported that background features related to chronic sun exposure and skin damage are frequently noted in sporadic melanoma but are rarely observed in FM [1].

Specific recommendations regarding the management of tumors in FM patients have not yet been formulated. At present, they are mostly treated according to the guidelines for the therapy of melanoma, with surgery being the cornerstone of treatment. The high risk of melanoma development in FM patients should, however, be taken into account when deciding on how to proceed with a suspicious lesion and usually inclines the balance towards its removal [4].

Despite cutaneous malignant melanoma being one of the most aggressive human cancers, high survival rates are reported for those detected at an early stage [5]. Advanced-stage melanoma, however, is related to a poor outcome, which highlights the importance of dermatological surveillance in patients prone to melanoma. Beyond that, data regarding the growth behavior of FM are scarce and inconsistent.

Individuals carrying mutations in the CDKN2A gene have been shown to have significantly worse survival than CDKN2A wild-type familial and sporadic melanoma patients, even though follow-up programs definitely contribute to an earlier diagnosis [3] [6]. This observation may imply greater melanoma invasiveness in case of mutated CDKN2A, but other factors should be considered that may add to mortality. Pancreatic and lung cancer, for instance, are more likely to affect those with CDKN2A mutations and have been described as a rather common cause of death in these patients. Another conclusion to be drawn from the aforecited study on survival in FM is that the individual prognosis largely depends on the genetic causes of FM.

In sum, the median overall survival of FM patients with and without mutations in the CDKN2A gene has been reported to be >25 and >30 years from the first diagnosis of melanoma, respectively [6].

The identification of a first gene conferring susceptibility to melanoma took place in the mid-1990s [7]. The CDKN2A gene has then been related to FM, but about a dozen other genes have since been linked to this type of cancer predisposition syndrome:

• Cutaneous malignant melanoma type 1 has been mapped to chromosome 1p36 but could not yet be associated with a specific gene. Similarly, types 4 and 7 of the disease have been mapped to chromosomes 1p22 and 20q11, respectively.
• Cutaneous malignant melanoma types 2, 3, 5, 6, 8, 9, and 10 are caused by mutations in genes CDKN2A (9p21), CDK4 (12q14), MC1R (16q24), XRCC3 (14q32), MITF (3p13), TERT (5p15), and POT1 (7q31), respectively.

It shall be mentioned that these same gene defects have also been related to a variety of other cancers, such as pancreatic, lung, and breast cancer as well as nervous system tumors and acute myeloid leukemia. They may also result in deafness, albinism and other pigmentation disorders, dyskeratosis, and pulmonary fibrosis, among others. These conditions may or may not develop in patients with melanoma, and in case of joint predisposition to more than one disease, years may pass between their respective diagnosis.

Furthermore, patients carrying certain variants of other genes may be predisposed to melanoma. Most of them are low-penetrance alleles that increase the hazard ratio by less than 2.5, which translates into a relatively low risk of skin cancer but major difficulties in recognizing family members who are likely to develop melanoma [7]. Contrary to the aforementioned high-risk types of FM, which are mostly inherited in an autosomal dominant manner, the latter are involved in a complex mode of inheritance.

In general, the penetrance of melanoma susceptibility genes may be modified by the same demographic, dermatological, and environmental factors that are generally associated with the development of skin cancer [8].

On a global scale, about 200,000 melanomas are diagnosed each year [9], and it has been estimated that about 1% of cutaneous melanomas occur in individuals with a strong family history of skin cancer [7]. Notwithstanding, the identification of high-risk gene defects is achieved in only a minor share of these cases. The majority of affected families likely harbors a number of genes contributing to and augmenting melanoma risk, and while we may not yet have understood the complex genetic background of these cases, they do form part of the entity discussed in this article.

The most common cause of melanoma susceptibility are mutations in the CDKN2A gene: They account for 30-40% of the families with three or more individuals with melanoma [7]. Other types of FM have been documented in only a small number of kindreds.

The majority of genes related to FM additionally confer risk to other cancers, indicating that they are likely general tumor suppressor genes or oncogenes [7]. Such has been shown for those melanoma susceptibility genes with the highest penetrance, namely CDKN2A, CKD4, TERT, and POT1 [5]. They are involved in cell-cycle regulation as well as telomere elongation and maintenance. In detail:

• CDKN2A encodes for cyclin-dependent kinase inhibitor 2A. Distinct variants of this protein are generated by alternative splicing; they function as an inhibitor of CDK4 kinase or act as a stabilizer of the tumor suppressor protein p53, both of which play key roles in progressing through the G1 phase of the cell cycle.
• CDK4 encodes for cyclin-dependent kinase 4, which is responsible for the phosphorylation of the retinoblastoma protein during G1-phase progression.
• The gene product of TERT has reverse transcriptase activity and maintains telomere ends by the addition of telomere repeats.
• POT1 encodes for one of the subunits of a multi-protein complex binding to those telomere repeats added by telomerase reverse transcriptase, thereby regulating telomere length and protecting chromosome ends.

Families known to harbor high-penetrance alleles predisposing to skin cancer should be offered genetic counseling [10]. Here, family members at risk may be identified through genetic studies and subsequently be included in surveillance programs. The latter should comprise biannual whole skin examinations including the scalp as well as the oral and genital mucosa [5].

Where multiple low-risk variants, which may not even be defined, contribute to a complex mode of inheritance, an individual risk assessment may pose a major challenge. Members of these families should be informed about general measures to reduce the risk of skin cancer, such as minimizing sun exposure [4]. Mutations induced by ultraviolet radiation are assumed to play key roles in the pathogenesis of both spontaneous and hereditary melanoma, with carriers of CDKN2A mutations living in regions with particularly high exposure to sunlight being most likely to develop FM: At the age of 80, about 91% of Australian carriers have been diagnosed with melanoma, 76% of those living in the United States, but only 58% of European patients [8]. These data emphasize that common skin cancer prevention strategies should also be recommended to FM patients.

In any case, members of melanoma families should be encouraged to realize skin self-examinations and undergo regular dermatological screenings. This should result in the early detection of suspicious lesions, which may subsequently be removed. Surgery at a premalignant stage is associated with a favorable prognosis [5] [7].

FM is a general term that refers to the hereditary predisposition to melanoma. The genetic background of FM is highly heterogeneous and remains incompletely understood. Mutations in the CDKN2A genes are the most common cause of FM and have a high penetrance. Several other genes have been identified that are involved in the pathogenesis of FM, but they are likely to be modified by as-of-yet unknown genetic and environmental factors. This complex setting poses a major challenge to genetic counselors and clinicians.

As of today, FM patients are included in surveillance programs and are treated much the same as sporadic melanoma patients upon the detection of suspicious lesions.

Melanoma is a common type of skin cancer. It is also one of the most aggressive human cancers, and preventive measures should be taken to lower the individual risk of developing melanoma. Because ultraviolet radiation has been identified as a main contributor to melanoma incidence, the general public is recommended to use sun protection and avoid excessive sun exposure. Notwithstanding, other factors do contribute to melanoma risk. Patients may carry mutations of specific genes that increase their susceptibility to this type of cancer. Such mutations are passed on from generation to generation, which results in familial clustering of melanoma. As per definition, familial melanoma (FM) is diagnosed when two first-degree relatives or three or more melanoma relatives on the same side of the family are diagnosed with melanoma.

Distinct mutations may account for FM, and they are associated with differences regarding the age at the first diagnosis of melanoma, with the likelihood of melanoma and other types of cancer, and the patient's prognosis. In general, patients with a hereditary predisposition to melanoma are diagnosed earlier than those suffering from sporadic skin cancer. Their mean age at the first diagnosis of melanoma may range between 37 and 46 years. They are also more likely to present multiple melanomas and to develop pancreatic, lung, or breast cancer. Accordingly, they should be included in surveillance programs and undergo biannual whole skin examinations as well as regular screenings for other types of cancer. These preventive measures allow for an earlier diagnosis of tumors, which substantially improves the prognosis.

Of note, ultraviolet radiation is a risk factor for FM, too. Patients carrying FM-related mutations should take the same preventive measures recommended to the general public.

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