Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies.

Despite genetics being accepted as the primary cause of familial aggregation for most diseases, it is still unclear whether afflicted families are likely to share a single highly penetrant rare variant, many minimally penetrant common variants, or a combination of the two types of variants. We therefore use recent estimates of SNP heritability and the liability threshold model to estimate the proportion of afflicted families likely to carry a rare, causal variant. We then show that Polygenic Risk Scores (PRS) may be useful for identifying families likely to carry such a rare variant and therefore for prioritizing families to include in sequencing studies with that aim. Specifically, we introduce a new statistic that estimates the proportion of individuals carrying causal rare variants based on the family structure, disease pattern, and PRS of genotyped individuals. Finally, we consider data from the MelaNostrum consortium and show that, despite an estimated PRS heritability of only 0.05 for melanoma, families carrying putative causal variants had a statistically significantly lower PRS, supporting the idea that PRS prioritization may be a useful future tool. However, it will be important to evaluate whether the presence of rare mendelian variants are generally associated with the proposed test statistic or lower PRS in future and larger studies.

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma.

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk  = 26.34), indicating good separation.

Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain.

BACKGROUND: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. OBJECTIVE: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. METHODS: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and noncarriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family. RESULTS: Histologic slides were evaluated for 290 melanomas (139 from 132 noncarriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, and 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in 10 of 15 invasive melanomas (67%) from POT1 carriers (P < .0001 vs noncarriers). This finding was independently confirmed by 3 expert melanoma dermatopathologists in 9 of 15 invasive melanomas (60%). In situ and invasive melanomas from CDKN2A and CDK4 carriers were histologically similar to melanomas from noncarriers. LIMITATIONS: Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1). CONCLUSION: Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoid differentiation in melanocytic tumors.

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

BACKGROUND: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved. METHODS: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics. RESULTS: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance. CONCLUSION: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.

MelaNostrum: a consensus questionnaire of standardized epidemiologic and clinical variables for melanoma risk assessment by the melanostrum consortium.

BACKGROUND: Many melanoma observational studies have been carried out across different countries and geographic areas using heterogeneous assessments of epidemiologic risk factors and clinical variables. AIM: To develop a consensus questionnaire to standardize epidemiologic and clinical data collection for melanoma risk assessment. METHODS: We used a stepwise strategy that included: compilation of variables from case-control datasets collected at various centres of the MelaNostrum Consortium; integration of variables from published case-control studies; consensus discussion of the collected items by MelaNostrum members; revision by independent experts; addition of online tools and image-based charts; questionnaire testing across centres and generation of a final draft. RESULTS: We developed a core consensus questionnaire (MelanoQ) that includes four separate sections: A. general and demographic data; B. phenotypic and ultraviolet radiation exposure risk factors and lifestyle habits; C. clinical examination, medical and family history; and D. diagnostic data on melanoma (cases only). Accompanying online tools, informative tables, and image-based charts aid standardization. Different subsections of the questionnaire are designed for self-administration, patient interviews performed by a physician or study nurse, and data collection from medical records. CONCLUSIONS: The MelanoQ questionnaire is a useful tool for the collection and standardization of epidemiologic and clinical data across different studies, centres, cultures and languages. This will expedite ongoing efforts to compile high-quality data for pooled analyses or meta-analyses and offer a solid base for the design of clinical, epidemiologic and translational studies on melanoma.

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Photodynamic therapy for the treatment of a giant superficial basal cell carcinoma.

A 74-year-old man was referred to our department for the treatment of a 15 x 15 cm superficial basal cell carcinoma (BCC) on his lumbar region. As surgical excision was considered too destructive, photodynamic therapy (PDT) was proposed. Methyl 5-aminolevulinate (MAL) cream was applied under occlusion for 3 h before illumination with a light-emitting diode lamp with an emission peak of 632 nm, a fluence rate of 83.3 mW/cm, and a light dose of 37 J/cm. A second MAL-PDT session was repeated 1 week later. The neoplastic area healed in 30 days. No recurrence has occurred after a 40-month follow-up period, but clinical observation continues. Although surgery still remains the treatment of choice for giant BCC, for which the local invasiveness and metastatic potential are well known, we offered our patient the option of PDT because we believed that classical surgery could hardly provide the same satisfactory outcome. As far as we know, this is the first case of giant BCC treated with PDT.

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents.

BACKGROUND: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. METHODS: These four features were examined in 385 families with > or =3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. RESULTS: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, > or =2 patients with MPM, median age at melanoma diagnosis < or =40 years and > or =6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only > or =1 patient with MPM and age at diagnosis < or =40 years simultaneously predicted the mutation risk. CONCLUSIONS: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.

Cutaneous cryptococcosis of the penis.

Disseminated cryptococcosis is a well-known opportunistic infection in AIDS patients. We report an unusual patient who demonstrated an isolated plaque of cryptococcosis on the penis. Resolution of this plaque was obtained after treatment with fluconazole, but subsequent cutaneous dissemination occurred that was responsive to amphotericin B.

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls.

BACKGROUND: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). METHODS: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS). RESULTS: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers. CONCLUSION: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.

Cutaneous melanoma in octogenarians: a single-institution review.

BACKGROUND: To identify the prognostic factors and assess the outcome of a group of octogenarian patients who were diagnosed with cutaneous melanoma (CM) in the Department of Dermatology of the "M. Bufalini" Hospital, Cesena, Italy from 1996 to 2013. METHODS: From the 1136 consecutive patients in our database, we selected 82 patients (7.2%) diagnosed with CM at age 80 or older. Their major clinical and histopathologic parameters were extracted and matched with those of the residual 1054 younger patients. RESULTS: Comparing our 82 patients with the group of 1054 patients with CM diagnosed in the same period, but at a younger age, we found that: 1) there was no significant difference regarding the patient's gender; 2) CM diagnosed in octogenarians was more frequently located on the head and neck (24.4% vs. 12.8%), and lower extremities (24.4% vs. 14.4%) (P=0.0001); 3) early diagnosis of CM (T1) was less frequent in octogenarians (31.7% vs. 62.6%), intermedium thickness CM (T2) was nearly the same in the 2 groups (15.8% vs. 16.5%), while diagnosis in category T3/T4 (42.6% vs. 21.0%) were significantly greater in octogenarians (P=0.0001); 4) ulceration was detected more frequently in octogenarians (18.3% vs. 10.7%) but the difference was not statistically significant. After a follow-up period of a median 58 months, 52 octogenarians (63.4%) were still alive and free from disease. Thirty of them (36.6%) had died, 14 (17.1%) of which because of melanoma. On the contrary, among the younger patients, 840 (81.6%) were alive, 132 (12.5%) died for melanoma and 75 (7.1%) for other causes. CONCLUSIONS: In our octogenarians, death for CM was not related to the old age but to the delayed diagnosis of cancer. Our results suggest that continuing educational programs for early diagnosis of CM should specifically include this segment of population.

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.

Congenital myofibromatosis in two siblings.

Infantile myofibromatosis (IM) is a rare mesenchymal disorder characterized by solitary or multiple nodules involving the skin, striated muscles, bones and, sometimes, viscera. Although most cases are sporadic, there have been a few reports of a familial pattern of inheritance. In most cases, diagnosing IM is not difficult. However, IM should be differentiated from neurofibromatosis, paediatric sarcomas, nodular fasciitis, fibrous hamartoma of infancy, and hyaline juvenile fibromatosis. The prognosis for IM depends on the degree of visceral involvement. Since spontaneous tumoral regression is usual, in cases of limited involvement therapeutic abstention and patient observation are recommended. Surgery, chemotherapy or radiotherapy are reserved for patients with multiple visceral localizations, particularly in the lung and gastrointestinal tract, which may have a worse prognosis and potentially fatal outcome. We report on a family in which two siblings, born from non-consanguineous parents, were affected by congenital myofibromatosis. In both patients, tumors were present at birth, with multicentric subcutaneous, muscular, skeletal and visceral involvement. The growing subcutaneous myofibromas were surgically removed, while the smallest ones disappeared spontaneously over the course of 24 months.

Maculo-papular rash induced by lopinavir/ritonavir.

Two patients with HIV disease developed a pruritic, maculo-papular rash shortly after introducing an association of 2 protease inhibitors (PI) lopinavir/ritonavir (Kaletra). The dermatitis started respectively 7 and 10 days after taking Kaletra, improved on withdrawal, and relapsed following its reintroduction. Although itchy, the dermatitis was not life-threatening, and the patients were treated "through the rash" without suspending the drug. Histopathologic examination of lesional skin showed a non-specific inflammatory infiltration consisting of neutrophils and lymphocytes, but there were no eosinophils, nor dilatation of capillaries in the papillary dermis. HIV positive patients are more prone to drug-related rashes than the general population. Awareness of the side-effects of PI plays an important role in keeping compliance with the treatment and helps patients reach their goal in controlling the development of HIV. The safety profile of Kaletra and its cutaneous side effects have yet to be completely elucidated.

Changing morbidity of cutaneous diseases in patients with HIV after the introduction of highly active antiretroviral therapy including a protease inhibitor.

BACKGROUND: Highly active antiretroviral therapy (HAART) is a combination of an HIV protease inhibitor (PI), one or two reverse transcriptase inhibitors (RTIs) and/or non-nuclease reverse transcriptase inhibitors (NNRTIs). This combination therapy is able to reduce peripheral HIV viral load, elevate CD4+ cell counts and improve the clinical outcome. AIM: To evaluate the impact of HAART therapy, including one PI, on the prevalence of skin diseases in patients with HIV/AIDS. PATIENTS AND METHODS: The study was performed by collecting data about HIV populations followed at the 'M. Bufalini' Infectious Diseases Unit and San Patrignano Medical Centre, Italy. The medical records regarding the dermatological diseases of such people were retrospectively examined in 12-month periods before (1996) and after (1999) the introduction of HAART. RESULTS: The two groups of patients were matched for age, gender and stage of HIV disease. During the first part of the study, 328 of the 456 patients (72%) sought medical advice 689 times for dermatoses. In the second period, 196 of the 502 patients (39%) made a total of 255 visits. There was a considerable decrease in the number of dermatological visits (-63%) and patients with dermatological problems (-40%). In the group that did not receive HAART, 66% of the patients had cutaneous infections, 25% had inflammatory cutaneous disorders, 8% adverse cutaneous drug reactions and 1% cutaneous neoplasms. In the group of patients treated with HAART, cutaneous infections were observed in 53% of patients, while 21% of patients had inflammatory dermatoses, 20% of patients showed adverse cutaneous drug reactions, and 1% had skin cancers. The remaining 5% asked to see a dermatologist for cosmetic reasons. CONCLUSIONS: The group of patients who received combination regimens including PIs had significantly lower cutaneous morbidity than those treated with nucleoside analogs alone. This tendency included both opportunistic infections and inflammatory cutaneous diseases. Adverse cutaneous drug reactions related to multidrug combination therapy were significantly higher in the group receiving HAART.

Topical 1% cidofovir for the treatment of basal cell carcinoma.

Cidofovir, a purine nucleotide analogue of deoxycytidine, is a drug effective against a wide number of DNA viruses. Recently, cidofovir has been supposed to exert antineoplastic activity, through the induction of apoptosis and the inhibition of angiogenesis. Four patients affected by basal cell carcinoma (BCC), who refused conventional surgery, were treated with a cream containing 1% cidofovir. The cream was applied every day for 10 days, then every other day for another 50 days. Histopathologic clearing was assessed with a skin biopsy performed on the previous lesional area 3 months after the end of treatment. All four patients achieved clinical healing of their lesion. Histological tumour regression was achieved in three patients. The treatment was well tolerated and the cosmetic results were excellent. No recurrences after an average 24-month follow up period were detected. The potential effectiveness of topical cidofovir for the non-surgical treatment of BCC have been shown. Nevertheless, appropriate clinical trials and prolonged follow-up periods are needed to confirm the efficacy and safety of topical cidofovir.

Blood DNA methylation, nevi number, and the risk of melanoma.

Germline mutations determining increased cutaneous malignant melanoma (CMM) risk have been identified in familial and sporadic CMM cases, but they account only for a small proportion of CMM cases. Recent evidence suggests that germline epimutations (e.g. DNA methylation alterations), which can be inherited similarly to genomic mutations and can be detected in normal body cells (including blood), might increase susceptibility to cancer. The aim of the study was to identify germline epimutations of genes that were found to be mutated in familial CMM (p16, p14, CDK4, MC1R, hTERT), immune and inflammatory genes (ICAM-1, TNFα), DNA mismatch repair gene (MLH1), and repetitive elements (ALU, LINE-1, HERV-w). We measured DNA methylation using bisulfite pyrosequencing in peripheral blood mononuclear cells from 167 CMM cases and 164 sex-matched and age-matched controls. We used multivariable logistic regression models to evaluate the association between methylation levels and CMM status or presence of dysplastic nevi. We found an association between the risk of CMM and peripheral blood mononuclear cell methylation levels of TNFα [odds ratio (OR)=1.11, 95% confidence interval (CI)=1.03-1.18], CDK4 (OR=0.76, 95% CI=0.64-0.91), and MLH1 (OR=1.12, 95% CI=1.02-1.22). In control participants, the risk of developing dysplastic nevi was associated with methylation levels of TNFα (OR=0.81, 95% CI=0.69-0.95), hTERT (OR=0.90, 95% CI=0.82-0.99), and ALU (OR=1.56, 95% CI=1.02-2.39). Epimutations in CMM susceptibility genes and in genes involved in response to oxidative damage are associated with the risk of developing CMM or dysplastic nevi. Further studies measuring methylation levels of these genes in prospectively collected samples are warranted to further elucidate their role in the development and progression of CMM.