CDK4 mutations are associated with a predisposition to melanocytic skin lesions, which may or may not be malignant [1]. While the majority of affected individuals is diagnosed with a single malignant lesion and several atypical nevi, about 40% of all patients develop multiple primary melanomas [2] [3]. Accordingly, patients often present with numerous skin lesions. They may also report that additional nevi or tumors have previously been removed.

CDK4-linked melanomas may develop on any area of the skin but are most commonly found on the limbs and trunk. Most are superficial spreading melanomas, which appear as flat, slowly growing lesions with irregular pigmentation and borders. They tend to enlarge in a radial manner [4]. While CDK4-linked lentigo maligna and nodular melanoma have also been reported, acral lentiginous melanoma has not yet been observed in carriers of CDK4 mutations [3]. Nevertheless, these epidemiological data suggest a wide variety in the presentation of CDK4-linked melanoma and point out that a clinical diagnosis of the disease is not feasible.

A detailed personal and familial history should be obtained to recognize the patient's predisposition to melanoma development and the genetic component in it. In this context, it should be noted that the penetrance of pathological CDK4 mutations is incomplete: The results of genealogical analyses may not indicate clear-cut Mendelian inheritance. Additionally, carriers of CDK4 mutations may not have been diagnosed with cutaneous melanoma but rather present with numerous atypical nevi, and intrafamilial differences regarding the age at onset of skin cancer may not allow for the unequivocal classification of living family members as affected or unaffected. While CDK4-linked melanoma is defined as an early-onset disease, with most patients being diagnosed in mid-adulthood, first melanomas have been reported to develop as late as in the ninth decade of life [3].

It is of major importance to realize a thorough dermatological examination. The presence of multiple clinically atypical nevi and/or primary melanomas should raise suspicion as to a genetic predisposition. Atypical nevi are asymmetric macular or maculopapular lesions that measure >5 mm in diameter, show irregular pigmentation patterns and ill-defined borders [2] [3]. Microscopic and immunohistochemical analyses are required to characterize single lesions, with diagnostic criteria applied to identify malignancy and histological subtypes not being different from those set in the general melanoma classification of the World Health Organization [4]. Nevertheless, these findings don't shed any light on the genetic causes of melanoma development.

Thus, in order to confirm the diagnosis of CDK4-linked melanoma, molecular biological studies have to be carried out. Due to the rarity of CDK4 mutations, most patients are initially tested for mutations of the CDKN2A gene. CDKN2A-linked melanoma is phenotypically indistinguishable from CDK4-linked disease but is much more common. In the absence of CDKN2A mutations, the CDK4 gene should be sequenced [2].

While the standard therapy of CDK4-linked melanoma continues to be the surgical resection of the tumor, distinct compounds are currently on trial for their efficacy in treating the disease [1] [5]. In detail, inhibitors of cyclin-dependent kinase 4 are developed to specifically downregulate the overactivated pathway involving cyclin-dependent kinase 4, its inhibitor p16, and retinoblastoma protein. Compounds that solely acted on cyclin-dependent kinase 4 have not yet been identified, but several inhibitors of cyclin-dependent kinases 4 and 6 have been extensively characterized. Three - ribociclib, palbociclib, and abemaciclib - have been approved for cancer therapy. They are used to treat breast cancer; evidence regarding their efficacy in melanoma patients has yet to be provided. The results of preliminary studies are encouraging, though, and whenever possible, members of families known to harbor CDK4 mutations should be included in clinical trials [6] [7].

Otherwise, recommendations for the treatment of CDK4-linked melanoma correspond to those given for cutaneous malignant melanoma in general [8] [9].

Causal treatment is not available, and patients carrying pathological CDK4 mutations are likely to develop additional skin lesions, even if a single tumor can successfully be removed. New malignancies have to be diagnosed early in order to prevent tissue invasion and metastasis, and to improve the outcome in affected individuals [10]. They should undergo regular follow-ups and preventive dermatological examinations, and be informed about the relevance of these measures: CDK4-linked melanoma has been reported to form metastases and lead to death [2].

The CDK4 gene encodes for cyclin-dependent kinase 4, the catalytic subunit of a serine-threonine kinase involved the regulation of the cell cycle. The gene is located on the long arm of chromosome 12 and comprises about 8.2 kb and eight exons. So far, all mutations related to an increased susceptibility to melanoma affect an arginine residue at amino acid position 24: In almost two-thirds of families known to carry pathological mutations of the CDK4 gene, the respective arginine residue is replaced by the amino acid histidine. In one-third of affected families, a lysine residue replaces arginine at position 24 [3]. Finally, a substitution of arginine by leucine, a non-basic amino acid, has been detected in a single family [1]. Genealogical analyses suggest an autosomal dominant inheritance of CDK4-related melanoma [2].

Malignant melanoma is a common type of skin cancer [10]. It has been estimated that 5-10% of all cases occur in a familial setting, and three genes have been identified as major contributors to increased susceptibility. One of them is the CDKN2A gene. CDKN2A mutations have a high penetrance and account for 20-40% of the aforementioned familial cases [11]. By contrast, germline mutations of the CDK4 gene have only been detected in a total of 18 families with an increased incidence of melanoma [1] [3]. The results of haplotype analyses argue against a common founder but rather suggest independent mutational events in families originating from different geographical regions [2]. With regard to the latter, the respective families reside in distinct European countries, Australia and the United States. In total, 62 of 89 family members who tested positive for CDK4 mutations were diagnosed with melanoma, and at the time of the first diagnosis of skin cancer, they had a mean age of 40 years. These data may suggest pathological variants of the CDK4 gene to have a penetrance of about 70%, but a large proportion of the remaining 27 individuals had clinically atypical nevi. Thus, the overall penetrance is likely >70% [3]. Of note, the third gene presumably implicated in increased susceptibility to melanoma is the MC1R gene [11]. Contrary to CDK4 and CDKN2A, MC1R is classified as a low-risk susceptibility gene [3].

Cyclin-dependent kinase 4 is required for the progression through the G1 phase of the cell cycle. Cyclin-dependent kinase 4 is the catalytic subunit of a complex formed with D-type cyclins, which fulfill regulatory functions. In order to avoid an accelerated progression through the G1 phase - which would be favoring tumor development -, cyclin-dependent kinase inhibitor p16 binds to this complex and lessens its activity. However, CDK4 mutations predisposing to melanoma are associated with an alteration of the p16 binding site of cyclin-dependent kinase 4 [12]. This results in an increased activity of the cyclin-dependent kinase 4/D-type cyclin complex [13].

p16 is encoded by the CDKN2A gene, which is another high-risk susceptibility gene for melanoma. Pathological mutations of the CDKN2A gene result in the inability of p16 to induce G1 cell cycle arrest, much like CDK4 mutations do. What's more, p16 depends on retinoblastoma protein, a tumor suppressor which is phosphorylated and deactivated by cyclin-dependent kinase 4. Overactivation of the pathway is thus avoided by a negative feedback loop comprising:

• The phosphorylation and deactivation of retinoblastoma protein by cyclin-dependent kinase 4
• The suppression of the inhibition of p16 by retinoblastoma protein in case of its phosphorylation
• The inhibition of cyclin-dependent kinase 4 by p16

Any interruption of this feedback loop favors the cell's progression to the S phase of the cell cycle. It has therefore been postulated that activating mutations of CDK4 as well as inactivating mutations of CDKN2A and RB1 trigger a common pathway of cancerogenesis [13]. This hypothesis is supported by the fact that CDK4-linked melanoma is phenotypically indistinguishable from CDKN2A-linked skin cancer [3].

It should further be noted that the CDK4 pathway is dysregulated in about 90% of all melanomas, regardless of mutations of the CDK4 gene [13]. Common driver mutations in malignant melanomas affect the BRAF and NRAS genes, and eventually cause an overexpression of D-type cyclins. The latter enhances CDK4-mediated signaling as depicted above. Consequently, the mechanisms described in this paragraph are of pathophysiological and therapeutic relevance not only for CDK4-linked melanoma but also for more common types of malignant melanoma.

Members of families known to harbor CDK4 mutations should be offered genetic testing. In case of positive results, they should be included in surveillance programs designed to detect skin cancer long before they reach the required age. CDK4-linked melanoma has been diagnosed in an 18-year-old patient, so regular dermatological examinations should be offered from adolescence [3]. Additionally, affected individuals should receive skin self-examination education [10].

Neither genetic nor environmental factors that increased the likelihood of developing cutaneous malignancies in case of pathological CDK4 mutations have been identified so far. Nevertheless, it may be assumed that excess exposure to sunlight and ultraviolet radiation may induce DNA damage that eventually potentiates preexisting disorders of cell cycle regulation [8] [10]. Carriers of pathological variants of CDK4 should therefore be recommended to use sunscreen, to wear long-sleeved clothes and wide-brimmed hats, and to avoid the full midday sun.

Both personal and familial medical histories affect an individual patient's risk to develop cutaneous melanoma. The risk augments by 5-8% in case of a previous diagnosis of skin cancer and further increases in those with a positive family history [11]. The latter may due to the presence of high-risk susceptibility genes like variants of CDK4: Germline mutations of the CDK4 gene strongly predispose to cutaneous melanoma [12]. The respective type of skin cancer may be referred to as CDK4-linked melanoma or cutaneous malignant melanoma 3, and is a very rare disease. The clinical presentation of CDK4-linked melanoma is non-specific, so genetic studies have to be realized to confirm the diagnosis.

Malignant melanoma is a common type of skin cancer. Both environmental and genetic factors are implicated in the development of this type of cutaneous malignancy: On the one hand, people with fair skin, blonde or red hair, and freckles have an increased risk of developing melanoma. Exposure to sunlight and ultraviolet radiation further augments an individual person's risk. On the other hand, patients may be genetically predisposed to cutaneous malignant melanoma. Families residing in Europe, Australia, and North America have been shown to harbor mutations in the CDK4 gene, to pass the respective gene from generation to generation, and to thereby inherit an increased susceptibility to skin cancer and non-cancerous dermatological lesions. In detail, affected family members are prone to develop clinically atypical nevi, which measure >5 mm in diameter, show irregular pigmentation patterns and ill-defined borders, and malignant tumors of the skin. The latter typically appear as flat, slowly growing lesions with irregular pigmentation and borders, but they may also grow as rapidly expanding, ulcerating nodules.

The diagnosis of CDK4-related melanoma requires genetic analyses and the identification of the causal mutation in the CDK4 gene. Beyond that, the characterization of single lesions is realized by means of histological studies. It is of major importance to recognize malignant lesions during early stages, so carriers of CDK4 mutations should participate in surveillance programs and learn how to self-examine their skin. This way, it is possible to reduce the likelihood of tissue invasion, metastatic spread, and death from skin cancer.

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