CDKN2A mutations in melanoma families from Uruguay

Background  Familial melanoma, a cluster of several cases within a single family, accounts for approximately 10% of cases of melanoma. Hereditary melanoma is defined as two or more first-degree relatives having melanoma. A member of a melanoma-prone family has a 35–70-fold increased relative risk of developing a melanoma. Genetic susceptibility is linked to the major susceptibility genes CDKN2A and CDK4 , and the minor susceptibility gene MC1R .
Objectives  To determine the clinical and genetic characteristics of cutaneous melanoma in melanoma-prone families from Uruguay.
Methods  We studied 13 individuals from six melanoma-prone families living in Uruguay. Phenotype, familial and personal history were recorded. Molecular screening of CDKN2A and CDK4 was done by polymerase chain reaction–single strand conformational polymorphism analysis. The MC1R gene was sequenced.
Results  Mutations in CDKN2A were detected in five of six families: c.−34G>T, p.G101W and p.E88X. A novel germline mutation p.E88X, associated with hereditary melanoma in two unrelated families, is described. We hypothesize that a founder effect occurred probably in the Mediterranean region. No mutations in CDK4 were detected. Six different MC1R variants, all previously reported, were present in Uruguayan families.
Conclusions  The overall rate of deleterious CDKN2A mutations in our familial melanoma pedigrees, even though the sample size is small, was considerably higher (83%) than the often quoted range.     

MC1R variation and melanoma risk in relation to host/clinical and environmental factors in CDKN2A positive and negative melanoma patients

Host, environmental and genetic factors differently modulate cutaneous melanoma (CM) risk across populations. Currently, the main genetic risk determinants are germline mutations in the major known high-risk susceptibility genes, CDKN2A and CDK4, and variants of the low-risk gene MC1R, which is key in the pigmentation process. This case-control study aimed at investigating the influence of the main host and environmental risk factors and of MC1R variation on CM risk in 390 CDKN2A-negative and 49 CDKN2A-positive Italian individuals. Multivariate analysis showed that MC1R variation, number of nevi and childhood sunburns doubled CM risk in CDKN2A-negative individuals. In CDKN2A-positive individuals, family history of CM and presence of atypical nevi, rather than MC1R status, modified risk (20.75- and 2.83-fold, respectively). Occupational sun exposure increased CM risk (three to sixfold) in both CDKN2A-negative and CDKN2A-positive individuals, reflecting the occupational habits of the Ligurian population and the geographical position of Liguria.     

Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma

Background The penetrance of CDKN2A mutations is subject to geographical and latitudinal variation and is presumably dictated by ultraviolet radiation exposure and possibly other co‐inherited genetic factors. The frequency of mutations increases with the number of family members affected and the number of primary tumours, and also fluctuates with geography. To date, little is known about the prevalence of CDKN2A mutations in patients with melanoma from Greece. Objective To characterize the frequency of CDKN2A and CDK4 mutations in a hospital‐based population of Greek patients with melanoma. Methods Three hundred and four consecutive single primary melanoma (SPM), nine familial melanoma (FM) and seven multiple primary melanoma cases (MPM) were assessed for sequence variants in exons 1α, 1β and 2 of CDKN2A and exon 2 of CDK4. Results Germline CDKN2A mutations were detected in 10 of 304 SPM (3·3%), in four of seven MPM (57%) and in two of nine FM (22%) cases. The most common mutation was a Northern European allele (p16 p.R24P) detected in eight individuals. Five previously unreported CDKN2A variants were also identified: ?34G>C, c.41_43delins20bp, c.301G>C (p.G101R), c.301G>A (p.G101E) and c.296_297insGACC. We also describe the first report of a CDK4 p.R24H substitution in a Greek family. Conclusions The Greek population appears to harbour a higher prevalence of the CDKN2A mutation than other reported cohorts. This supports the notion that genetic susceptibility may play a stronger influence in a country with a relatively low incidence of melanoma. Furthermore, the identification of Northern European alleles suggests that gene migration may be responsible, in part, for the observed cases in Greece.     

Genetic determinants of cutaneous melanoma predisposition

In the last 2 decades, advances in genomic technologies and molecular biology have accelerated the identification of multiple genetic loci that confer risk for cutaneous melanoma. The risk alleles range from rarely occurring, high-risk variants with a strong familial predisposition to low-risk to moderate-risk variants with modest melanoma association. Although the high-risk alleles are limited to the CDKN2A and CDK4 loci, the authors of recent genome-wide association studies have uncovered a set of variants in pigmentation loci that contribute to low risk. A biological validation of these new findings would provide greater understanding of the disease. In this review we describe some of the important risk loci and their association to risk of developing cutaneous melanoma and also address the current clinical challenges in CDKN2A genetic testing.     

Malignant Melanoma–a Genetic Overview

Malignant melanoma, a potentially lethal skin neoplasm, is characterized by a complex and heterogeneous etiology. Both incidences and deaths associated with melanoma are increasing in Caucasian populations. While exposure to ultraviolet radiation through sun-exposure is the major risk factor; the host factors including skin type and number of moles are critical in predisposition. The CDKN2A is a high penetrance melanoma susceptibility gene as carriers of the mutations are predisposed to the disease within familial settings. The gene is also somatically altered to varying degrees in sporadic melanoma. The CDK4 gene due to occurrence of activation mutations in a few families worldwide represents another melanoma susceptibility locus. The variants within the melanocortin receptor 1 (MC1R) gene, which encodes a melanocyte specific surface receptor with a key role in pigmentation, are associated with high risk phenotypes and increased risk of melanoma. Melanoma tumors are characterized by activation of the RAS-RAF-MEK-ERK pathway through either autocrine growth factor stimulation or oncogenic mutations in the B-RAF or N-RAS genes. Somatic mutations in the B-RAF gene are complemented by those in the N-RAS gene and represent the major genetic alterations. The mutations in the B-RAF gene in melanoma due to occurrence in melanocytic nevi represent early events that additionally require loss of cell cycle inhibitors like CDKN2A for melanoma progression and development. The sequence of events points to the cooperative collaboration between different genetic pathways in tumor development that can be and are being used as targets for developing specific therapeutic agents.     

Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients

Abstract:  The risks of developing malignant melanoma (MM) include ultraviolet irradiation and genetic factors. To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A ( CDKN2A ), cyclin-dependent kinase 4, melanocortin 1 receptor ( MC1R ) and tyrosinase ( TYR )] were resequenced in 109–135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R 'R' variants known or predicted to alter its function ( P  = 0.002), particularly the R160W variant ( P  = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer.     

Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma

BACKGROUND: In patients with cutaneous melanoma, early age at disease onset is characteristic in familial cases and in individuals with multiple primary melanomas. Both subsets of patients with melanoma are at risk for harboring germline CDKN2A or CDK4 mutations. OBJECTIVE: We set out to prospectively determine the prevalence of CDKN2A and CDK4 mutations in a group of young patients with melanoma. DESIGN: We prospectively screened 913 patients over a 6-month period and identified 519 patients with invasive melanomas. We invited 172 patients with melanoma who were younger than 40 years to participate in the study, and 49 patients consented and donated peripheral blood samples. Forty-nine percent (n = 24) of our patients developed cutaneous melanoma before the age of 30 years. SETTING: A melanoma clinic in the Boston, Mass, area. MAIN OUTCOME MEASURE: We used a combination of single-strand conformation analysis and direct sequencing of samples of peripheral blood leukocyte DNA to search for mutations in exons 1alpha, 1beta, 2, and 3 of CDKN2A and in exon 2 of CDK4. RESULTS: The mean and median ages at diagnosis in our group were 30 and 32 years, respectively. Among a group of 49 patients, we detected 1 (2%; 95% confidence interval, 0.07%-10.8%) Met 53 Ile CDKN2A mutation, which was found in a patient with a strong family history of melanoma. This alteration has been previously shown to impair p16 function. One patient had an Ala 148 Thr change in CDKN2A, which has also been shown to be a polymorphism. We also detected a sequence polymorphism (in the 3' untranslated region [3'UTR] of CDKN2A) in 27% of our patients. A similar incidence of this 3'UTR polymorphism was observed in a control population. We found no CDK4 mutations. CONCLUSIONS: Germline CDKN2A and CDK4 mutations are not common in patients who develop melanoma at an early age. This finding contrasts with other cancer-predisposition syndromes, in which there is an increased incidence of germline mutations among young patients. Selection of patients with melanoma for genetic testing based solely on age at onset may not be warranted at the current time.     

Evaluation of germline CDKN2A, ARF, CDK4, PTEN, and BRAF alterations in atypical mole syndrome

Atypical mole syndrome is a sporadic or an inherited condition with an increased risk of melanoma. Germline mutations in the CDKN2A, ARF, CDK4 and somatic mutations in the PTEN and BRAF genes have been associated with melanoma. In this study, we evaluated genes associated with familial and sporadic melanoma for mutations in 28 probands with the atypical mole syndrome. No sequence alterations in the coding regions or in the splice junctions of CDKN2A, ARF, CDK4, PTEN or BRAF were identified. These data suggest that genes evaluated in this study are unlikely to be candidate genes for atypical mole syndrome and support the notion that unknown susceptibility gene/s for this disease exist.     

Multiple melanomas after treatment for Hodgkin lymphoma in a non-Dutch p16-Leiden mutation carrier with 2 MC1R high-risk variants

BACKGROUND: A 19-base pair germline deletion in exon 2 of the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene (Leiden mutation) has been detected in Dutch families with familial melanomas. The penetrance of CDKN2A mutations varies widely and is influenced by environmental and unrelated genetic factors such as variants in the MC1R gene. OBSERVATIONS: We describe a 25-year-old German woman who developed 8 invasive melanomas and 6 in situ melanomas after radiation therapy and polychemotherapy for Hodgkin lymphoma. Genetic testing revealed a constitutional CDKN2A Leiden mutation in the proband and her sister, mother, and mother's sister. The proband also carried high-risk MC1R variant alleles R151C and R160W, which she had inherited from her father and her mother, respectively. The less affected mutation carrier sister did not have high-risk MC1R variant alleles. Analysis of DNA from paraffin-embedded tissues showed loss of heterozygosity at CDKN2A loci in all 3 melanomas studied but not in Hodgkin lymphoma. The pedigree revealed several types of cancers on both sides of the family, but no Dutch ancestors were found. No mutations in the CDK4, B-raf, and N-ras genes were detected either in the germline or in tumors from the patient. CONCLUSION: This study shows the variability of the penetrance of the CDKN2A Leiden mutation within the same family, which could be due to genetic or exogenous factors.     

A flexible multiplex bead-based assay for detecting germline CDKN2A and CDK4 variants in melanoma-prone kindreds

The presence of recurrent high-risk mutations in cyclin-dependent kinase inhibitor 2A/cyclin-dependent kinase 4 (CDKN2A/CDK4) among melanoma-prone families suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. To this end, we have developed a multiplex bead-based assay for high-throughput CDKN2A/CDK4 genotyping in the context of familial melanoma. Genomic DNA from 1,603 subjects (1,005 in training set and 598 in validation set) were amplified by multiplex PCR using five CDKN2A/CDK4 primer sets followed by multiplex allele-specific primer extension for 39 distinct germline variants. The products were then sorted and analyzed using the Luminex xMAP system. Genotypes were compared with previously determined sequence data. In the Toronto training cohort, all 145 samples with known variants were detected by the bead assay (100% concordance). Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77%). Overall, the bead assay correctly genotyped 1,540/1,603 (96.07%) of all individuals in the study and 1,540/1,545 (99.68%) of individuals whose variants were represented in the probe set. Out of a total of 62,517 allelic calls, 62,512 (99.99%) were correctly assigned. The multiplex bead-based assay is an accurate method for genotyping CDKN2A/CDK4 variants and is potentially useful in genotyping low-to-moderate melanoma risk single-nucleotide polymorphisms.     

Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A,MC1R and HERC2/OCA2

Please cite this paper as: Genetic analysis of three important genes in pigmentation and melanoma susceptibility: CDKN2A, MC1R and HERC2/OCA2. Experimental Dermatology 2010; 19 : 836–844. Abstract: The CDKN2A gene is regarded as the major familial malignant melanoma (MM) susceptibility gene. Human pigmentation is one of the main modulators of individual risk of developing MM. Therefore, the genes involved in the determination of skin colour and tanning response are potentially implicated in MM predisposition and may be useful predictors of MM risk in the general population. The human melanocortin‐1 receptor gene (MC1R) plays a crucial role in pigmentation and also appears to be important in MM. The OCA2 gene has emerged as a new and significant determinant of human iris colour variation. We present a case–control study in Spanish population including 390 consecutive patients with melanoma and 254 control subjects. Sequence analysis of the entire coding region and genotyping of 5 tag‐SNPs in the genomic region of MC1R was performed. We identified 27 variants, two reaching statistical significance [R160W (OR: 4.18, 95% CI: 1.24–14.04, P = 0.02) and D294H (OR: 3.10, 95% CI: 1.37–7.01, P = 0.01)] and we detected two novel non‐synonymous changes: V92L and T308M. Odds ratio for carrying two functional variants was 4.25 (95% CI: 2.30–7.84, P = 3.63 × 10^?6). Haplotypes of the entire MC1R region have been established, and we observed an enrichment of a rare European haplotype similar to African values carrying variants V92M and I155T. In addition, three potentially functional SNPs were selected in p16/CDKN2A and in the promoter region of OCA2/HERC2. Our data for CDKN2A gene did not reach statistically significant results for any of the two studied alleles. We found that the variant allele A > G of OCA2/HERC2 (rs12913832) was associated with pigmentation features: eye, hair and skin colour; P‐values = 1.8 × 10^?29, 9.2 × 10^?16, 1.1 × 10^?3, respectively, validating previous results.     

Dermoscopic features of melanomas associated with MC1R variants in Spanish CDKN2A mutation carriers

BACKGROUND: The presence of at least one MC1R gene variant is associated with a reduction in age at melanoma diagnosis in families with CDKN2A mutations. OBJECTIVES: To describe dermoscopic features of early melanoma in CDKN2A gene mutation-positive Spanish individuals and to evaluate the possibility of a correlation between particular dermatoscopic pattern and MC1R gene variants. METHODS: Patients in whom a melanoma was diagnosed during specific follow up of high-risk individuals carrying CDKN2A mutations (with familial or personal history of previous melanoma) were included in this study. The decision to remove such melanomas was taken on the basis of history, clinical and dermoscopic evaluations including total body photography and digital dermoscopy. RESULTS: Of the nine patients included in this study, three were noncarriers of the red hair MC1R polymorphism, three patients had one red hair MC1R polymorphism and three patients had two red hair MC1R polymorphisms. On dermoscopic analysis of suspect melanocytic lesions we found that the mean +/- SD ABCD total dermoscopy score (TDS) was significantly higher in noncarriers of red hair MC1R polymorphisms than in carriers of two MC1R gene red hair variants (6.8 +/- 0.4 vs. 4.4 +/- 0.9; P = 0.014). CONCLUSIONS: Early melanomas in patients with two MC1R red hair variants may be difficult to diagnose definitively by dermoscopy because, in our limited experience, they show fewer colours and structures and have a lower TDS. In such melanomas, subtle atypical vessels and other changes detected by digital image follow up may be useful to confirm the diagnosis of melanoma. An integrated approach including clinical history and dermoscopic data (also considering additional information, such as the presence of atypical vessels) should be utilized in evaluating these high-risk patients. Further studies are necessary to confirm our suggestion.     

Genetic predisposition in cutaneous melanoma

The incidence of cutaneous melanoma has increased worldwide in the last 20 years. Research on potential risk factors, both environmental and genetic, has led us to some new and interesting conclusions. Ultraviolet radiation is clearly the main environmental risk factor for melanoma, but its relationship is complex and controversial. With regard to genetic factors, the discovery of two types of genes was a great advance in further understanding the biology of the melanocyte. CDKN2A (p16) is the prototype of the high-penetrance, low-prevalence gene related to melanoma. This gene has been studied in some families in which several members have been diagnosed with melanoma. In the general population with non-familial melanoma, low-penetrance, high-prevalence genes such as MC1R seem to be more interesting. Studies on the MC1R gene have not only shown its importance in skin and hair pigmentation, but also in the development of melanoma. Functional studies on CDKN2A and MC1R have led us to new and important conclusions. The analysis of data from studies on families, twins and control cases, with the collaboration of several countries, will lead us to new discoveries. For the primary and secondary prevention of this tumor, we must promote public health campaigns on the dangers of sun exposure and the identification of individuals at high risk.     

Genotype analysis in Hungarian patients with multiple primary melanoma

Multiple primary melanoma patients (MPMps) have better prognosis and are more prone to genetic predisposition than single melanoma patients. We aimed to compare genetic background (CDKN2A, CDK4, MITF, MC1R) of 43 Hungarian MPMps with their clinicopathological data. We observed a higher rate of synchronous first and second melanoma (MM) (49%) and a higher frequency of non‐melanoma tumor co‐occurrence (42%) than reported previously. CDKN2A mutation frequency was 4.7% (E69G, R99P). We identified a new human MC1R variant (D117G) and reported MC1R variant distributions in Hungarian MMs for the first time. The rare R163Q was exceptionally common among Hungarian MPMps, a variant otherwise frequent in Asia, but not in Europe. MC1R ‘R’ carriers showed histopathological signs of a more progressive disease than ‘r’ carriers did; however, tumor‐infiltrating lymphocytes (TILs) in their second melanomas occurred significantly more frequently. Calculating 5‐year overall survival, ‘R’ carriers showed more unfavourable prognosis (87%) than ‘r’ carriers did (95%).     

Melanocortin receptor-1 gene polymorphisms and the risk of cutaneous melanoma in a low-risk southern European population

Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI) = 1.50-3.96, P < 0.001) for melanoma among MC1R carriers. The risk of melanoma was enhanced in individuals carrying multiple variant alleles (OR = 6.97; 95% CI = 1.86-26.12, P = 0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.     

Novel CDKN2A mutation detected in Spanish melanoma pedigree

Please cite this paper as: Novel CDKN2A mutation detected in Spanish melanoma pedigree. Experimental Dermatology 2010; 19 : e333–e335. Abstract: We have examined alterations in the cyclin‐dependent kinase inhibitor 2A (CDKN2A) and cyclin‐dependent kinase 4 (CDK4), major melanoma predisposing genes, in a Spanish melanoma‐prone population comprising 61 patients from 45 families. Using an extensive genetic analysis of these genes, including sequence analysis and multiplex ligation‐dependent probe amplification, we have found four different CDKN2A alterations in cases from seven melanoma kindred. Three of them are CDKN2A mutations previously described in the Mediterranean population (p.G101W, p.V59G and c.358delG) in addition to an undescribed deletion (p. M54del) which has been detected in a melanoma kindred. This codon deletion affects an essential residue in the interaction of p16INK4A with cdk6 and has not been reported in melanoma patients and other cancers.     

Melanoma and genetics

As the incidence of malignant melanoma continues to increase and with the completion of the sequencing of the human genome, there have been increasing efforts to identify the “melanoma gene(s).” Although some patients and families have significantly increased risks due to genetic predisposition, most melanoma cases are sporadic and likely result from low to moderate risk genetic factors. This review focuses on the genes that cover the greatest risk of developing melanoma. It is important to remember that many—if not most—cases of melanoma are the result of undiscovered variants. The strongest genetic risk for the development of melanoma results from heritable alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which encodes two separate but related proteins, p16/^INK4a and p14/^ARF. These proteins help regulate cell division and apoptosis, both of which are necessary to maintain cellular homeostasis. Other important genes include CDK4/6 and retinoblastoma (RB1), which encode downstream proteins in the same pathway as p16/^INK4a and p14/^ARF. Finally, we discuss the relative importance of the melanocortin 1 receptor (MC1R) gene as a moderate risk factor for melanoma. Although great advances have been made in understanding the molecular basis and genetic predisposition of melanoma, many questions still remain to be answered. Someday soon, it will be possible to predict a patient's risk of melanoma by DNA analysis; however, it is important to reconcile our tremendous technologic capabilities with documented clinical utility.     

Clinical and molecular characterization of patients at risk for hereditary melanoma in southern Brazil

Melanoma is the most dangerous of all common skin cancers, due to its propensity to metastasize. Therefore, identification of at-risk populations may allow early detection of disease at a curable stage. In Europe and North America, between 8-14% of melanoma patients have a family history of the disease, and a subset of these individuals possess germline mutations in the CDKN2A gene, which encodes the p16(INK4A) and p14(ARF) tumor suppressors. We identified 30 patients (29 families) from Southern Brazil, who had a family history of melanoma and/or pancreatic cancer; or a personal history of multiple primary melanoma. We screened this cohort for mutations in the CDKN2A and CDK4 genes, and detected two functional mutations: a G-34T transversion in 5'untranslated region; and a M53I alteration encoded in exon 2. Both mutants have been previously associated with melanoma and demonstrate founder effects. We conclude that germline mutations of CDKN2A occur in the Brazilian population, and that these mutations likely originated in Europe.     

CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients

Non‐invasive diagnostic tools are effective in the histomorphological study of melanocytic lesions. The role of melanoma susceptibility genes on melanocytic nevi histopathological features is not clear. The current study aimed to correlate genetic alterations and histomorphological features of melanocytic nevi. Clinical, dermoscopic and confocal features of 34 multiple melanoma patients and 34 controls were compared. Among patients with melanoma, carriers of CDKN2A mutations and/or MC1R variants, and wild‐type genes were also compared. In patients with melanoma, a lighter phototype (P = 0.051), a higher number of nevi (P < 0.01) and clinically atypical nevi (P < 0.01) were observed. At dermoscopy, these nevi showed a complex pattern (P = 0.011), atypical network (P = 0.018) and irregular pigmentation (P = 0.037); at confocal, an irregular meshwork pattern (P = 0.026) with atypical nests (P = 0.016) and an inflammatory infiltrate (P = 0.048) were observed. Among patients with melanoma genetically tested, CDKN2A G101W mutation carriers were more frequently younger (P = 0.023), with clinically atypical nevi (P = 0.050), with cytological atypia (P = 0.033) at confocal. G101W mutation and MC1R variants carriers showed hypopigmented nevi (P = 0.002) and, at confocal, roundish cells infiltrating the junction (P = 0.019). These data suggest an influence of CDKN2A mutation and MC1R variants in the development of dysplastic melanocytic lesions. Non‐invasive histomorphological evaluation, together with genetic studies, improves melanoma risk identification and early diagnosis, for a patient‐tailored management.     

Analysis of the CDKN2A and CDK4 genes and HLA-DR and HLA-DQ alleles in two Spanish familial melanoma kindreds

Some confusion exists in the literature about which criteria should be used to define familial melanoma. This could explain the different reported frequencies of mutations in predisposing genes, mostly CDKN2A, in these patients. This study evaluated the human leucocyte antigen (HLA) class II genotype and the presence of mutations in CDKN2A and CDK4 genes in 2 families with very different clinical features. The family with a germinal mutation in exon 2 of CDKN2A (Gly101Try) presented the following clinical features: 3 first-degree affected members, 1 of whom had 2 melanomas, and all the melanomas appearing before 35 years of age. In contrast, the second family did not present any mutation in the studied genes and included 2 first-degree affected members diagnosed at over 45 years of age. Neither family showed an association with HLA genotype. Other genes are also involved in familial melanoma but, when the CDKN2A gene is affected, some clinical features seem to be uniform.