Melanoma-prone Families Research Articles

Abstract 5050: Germline variants in CDKN2A wild-type melanoma prone families

Abstract The presence of germline pathogenic variants in CDKN2A is a well-established underlying cause of familial malignant melanoma. While pathogenic variants in several other genes have also been linked to melanoma development, many familial cases remain unexplained. We analyzed for pathogenic germline variants in a panel of 360 cancer related genes in a set of 56 Norwegian melanoma prone families. The index cases and families were selected based on familial history of melanoma and/or multiple primary melanomas in the same individual, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants. These variants were found in BRCA2, MRE11, ATM, MSH2, CHEK2 and AR. In addition, one family member with a melanoma diagnosis (not index case) carried a pathogenic variant in MAP3K6. In genes typically linked to xeroderma pigmentosum, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance. In particular the XPCL48F variant was found in 8 out of 56 indexes, thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (p-values from 0.007 to 0.014). Similarly, we found presumed benign or uncertain variants in MC1R to be significantly enriched or numerically higher in index cases versus comparable healthy populations (p-values from 0.009 to 0.1). The common MC1RArg151Cys variant was highly enriched in our cohort (p=0.001).In conclusion, we found that several melanoma prone families harbored pathogenic variants in genes not usually linked to melanoma. Citation Format: Stian Knappskog, Gjertrud T. Iversen, Marie Loeng, Amalie L. Holth, Per E. Lonning, Jurgen Geisler. Germline variants in CDKN2A wild-type melanoma prone families [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5050.

Copy number variations in malignant melanoma: genomic regions, biomarkers, and therapeutic targets.

Malignant melanoma is a skin tumor arising from melanocytes, occurring mostly in predisposed individuals. Melanomas are frequently present with copy number variations (CNVs), i.e., gains or losses of specific DNA regions that have provided immense potential for disease diagnosis and classification. The methodology of CNV detection has revolutionized in past decades, and current high throughput technologies enable us to analyze the entire spectrum of CNV alterations at the whole genome scale. Thus, identifying novel CNV biomarkers and evaluating their applicability in biomedicine are becoming increasingly important. The aim of this review was to summarize copy number changes occurring in malignant melanomas. We made an overview of specific genes and chromosomal locations affected in sporadic and familial melanoma and also of known germline alterations in melanoma-prone families. We summarized genomic regions aberrant in malignant melanoma and highlighted those frequently discussed in the literature, suggesting 7q, 11q, 12q, 9p, and 1q, but also others, as the most affected ones.

Characterization of Potential Melanoma Predisposition Genes in High-Risk Brazilian Patients

Increased genetic risk for melanoma can occur in the context of germline pathogenic variants in high-penetrance genes, such as CDKN2A and CDK4, risk variants in low- to moderate-penetrance genes (MC1R and MITF), and possibly due to variants in emerging genes, such as ACD, TERF2IP, and TERT. We aimed to identify germline variants in high- and low- to moderate-penetrance melanoma risk genes in Brazilian patients with clinical criteria for familial melanoma syndrome. We selected patients with three or more melanomas or melanoma patients from families with three tumors (melanoma and pancreatic cancer) in first- or second-degree relatives. Genetic testing was performed with a nine-gene panel (ACD, BAP1, CDK4, CDKN2A, POT1, TERT, TERF2IP, MC1R, and MITF). In 36 patients, we identified 2 (5.6%) with germline pathogenic variants in CDKN2A and BAP1 and 4 (11.1%) with variants of uncertain significance in the high-penetrance genes. MC1R variants were found in 86.5%, and both red hair color variants and unknown risk variants were enriched in patients compared to a control group. The low frequency of germline pathogenic variants in the high-penetrance genes and the high prevalence of MC1R variants found in our cohort show the importance of the MC1R genotype in determining the risk of melanoma in the Brazilian melanoma-prone families.

Interactive Beliefs about Genes and Behavior Predict Improved Sun Protection Following Melanoma Genetic Counseling.

Little is known about how members of cancer-prone families think about genetic determinism and whether personal behavior can amplify or counter genetic risk for disease. Understanding how people think about the impact of personal behavior on disease risk may inform communications about genetic risks and their management. We assessed three sets of beliefs about the impact of behavior on genetic risk-interactive (unhealthful behaviors can amplify genetic risk), subtractive (healthful behaviors can reduce genetic risk), and deterministic (genes primarily determine health outcomes)-among 114 unaffected members of melanoma-prone families receiving genetic counseling (51.6% men, average age = 35.3). We examined whether these beliefs predicted changes in perceived control, motivation to manage melanoma risk, and sun-protection behavior one year later. Participants strongly endorsed interactive and subtractive beliefs, but not deterministic beliefs. These beliefs generally did not change, even among those who received positive CDKN2A/p16 genetic test results conferring up to 76% lifetime melanoma risk. Controlling for age, sex, education, skin type, and genetic test result, interactive beliefs predicted sustained increases in perceptions of personal control, motivation to reduce sun exposure, use of multiple sun-protection methods, and reduction in objectively assessed tanning at the wrist one year following genetic counseling. Subtractive beliefs predicted increased personal control, motivation to manage risk, and sunscreen use, while deterministic beliefs were generally unrelated to outcomes. Among people at highly elevated hereditary cancer risk, beliefs that unhealthful behaviors can amplify genetic risk seem to be especially motivating of behavioral risk-reduction efforts.

Integrated Analysis of Coexpression and Exome Sequencing to Prioritize Susceptibility Genes for Familial Cutaneous Melanoma

The application of whole-exome sequencing has led to the identification of high- and moderate-risk variants that contribute to cutaneous melanoma susceptibility. However, confirming disease-causing variants remains challenging. We applied a gene coexpression network analysis to prioritize the candidate genes identified from whole-exome sequencing of 34 melanoma-prone families, with at least three affected members sequenced per family (N= 119 cases). A coexpression network was constructed from genotype-tissue expression project, skin melanoma from the cancer genome atlas, and primary melanocyte cultures. We performed module-specific enrichment and focused on modules associated with pigmentation processes because they are the best-studied and most well-known risk factors for melanoma susceptibility. We found that pigmentation-associated modules across the four expression datasets examined were enriched for well-known melanoma susceptibility genes plus genes associated with pigmentation. We also used network properties to prioritize genes within pigmentation modules as candidate susceptibility genes. Integrating information from coexpression network analysis and variant prioritization, we identified 36 genes (such as DCT, TPCN2, TRPM1, ATP10A, and EPHA5) as potential melanoma risk genes in the families. Our approach also allowed us to link families with private gene mutations on the basis of gene coexpression patterns and thereby may provide an innovative perspective in gene identification in high-risk families.

Family-based whole-exome sequencing identifies rare variants potentially related to cutaneous melanoma predisposition in Brazilian melanoma-prone families.

Genetic predisposition accounts for nearly 10% of all melanoma cases and has been associated with a dozen moderate- to high-penetrance genes, including CDKN2A, CDK4, POT1 and BAP1. However, in most melanoma-prone families, the genetic etiology of cancer predisposition remains undetermined. The goal of this study was to identify rare genomic variants associated with cutaneous melanoma susceptibility in melanoma-prone families. Whole-exome sequencing was performed in 2 affected individuals of 5 melanoma-prone families negative for mutations in CDKN2A and CDK4, the major cutaneous melanoma risk genes. A total of 288 rare coding variants shared by the affected relatives of each family were identified, including 7 loss-of-function variants. By performing in silico analyses of gene function, biological pathways, and variant pathogenicity prediction, we underscored the putative role of several genes for melanoma risk, including previously described genes such as MYO7A and WRN, as well as new putative candidates, such as SERPINB4, HRNR, and NOP10. In conclusion, our data revealed rare germline variants in melanoma-prone families contributing with a novel set of potential candidate genes to be further investigated in future studies.

Novel loss-of-function variant in DENND5A impedes melanosomal cargo transport and predisposes to familial cutaneous melanoma

PurposeMore than half of the familial cutaneous melanomas have unknown genetic predisposition. This study aims at characterizing a novel melanoma susceptibility gene. MethodsWe performed exome and targeted sequencing in melanoma-prone families without any known melanoma susceptibility genes. We analyzed the expression of candidate gene DENND5A in melanoma samples in relation to pigmentation and UV signature. Functional studies were carried out using microscopic approaches and zebrafish model. ResultsWe identified a novel DENND5A truncating variant that segregated with melanoma in a Swedish family and 2 additional rare DENND5A variants, 1 of which segregated with the disease in an American family. We found that DENND5A is significantly enriched in pigmented melanoma tissue. Our functional studies show that loss of DENND5A function leads to decrease in melanin content in vitro and pigmentation defects in vivo. Mechanistically, harboring the truncating variant or being suppressed leads to DENND5A losing its interaction with SNX1 and its ability to transport the SNX1-associated vesicles from melanosomes. Consequently, untethered SNX1-premelanosome protein and redundant tyrosinase are redirected to lysosomal degradation by default, causing decrease in melanin content. ConclusionOur findings provide evidence of a physiological role of DENND5A in the skin context and link its variants to melanoma susceptibility.

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.

Genetic markers for characterization and prediction of prognosis of melanoma subtypes: a 2021 update.

In this article we examined the most important genetic markers involved in melanoma susceptibility, initiation and progression, and their impact on the prognosis of the disease. Current knowledge in melanoma genetics identifies distinct pathways to the development of different melanoma subtypes characterized by specific clinico-pathological features and partially known genetic markers, modulated by high, low or absence of cumulative sun damage. The most prevalent somatic mutations are related to the activation of the MAPK pathway, which are classified into four major subtypes: BRAF mutant, NRAS mutant, NF1 mutant and triple wild type. Moreover, germinal mutations are also involved in the characterization and predictions of prognosis in melanoma. Currently, CDKN2A is seen as the main high-risk gene involved in melanoma susceptibility being mutated in around 20% of melanoma-prone families. Other high-risk susceptibility genes described include CDK4, POT1, BAP1, TERT promoter, ACD, and TERF2IP. Melanoma is one of the most genetically predisposed among all cancers in humans, and ultraviolet light from the sun is the main environmental factor. This genetic predisposition is starting to be understood, impacting not only on the risk of developing melanoma but also on the risk of developing other types of cancer, as well as on the prognosis of the disease.

Increased Risk of Skin Cancer in 1,851 Long-Term Retinoblastoma Survivors

Patients with hereditary retinoblastoma are at risk for developing cutaneous melanoma, but little is known about the role of sun exposure or other factors, and the incidence of nonmelanoma skin cancer (NMSC) is poorly understood. We investigated the incidence of melanoma and NMSC in a cohort of 1,851 White, long-term retinoblastoma survivors (1,020 hereditary and 831 nonhereditary) diagnosed during 1914‒2006. During follow-up through 2016, 33 hereditary and 7 nonhereditary survivors developed melanoma, and 26 hereditary and 9 nonhereditary survivors developed NMSC. Most NMSCs were on the head/neck, whereas melanomas were more broadly distributed with patterns similar to melanoma-prone families. For both outcomes, the median age at diagnosis was ~20 years younger among hereditary survivors than among nonhereditary survivors. At 50 years after retinoblastoma diagnosis, the cumulative incidence in hereditary survivors was 4.5% for melanoma and 3.7% for NMSC; for nonhereditary survivors, it was 0.7% and 1.5%, respectively. Sun sensitivity and phenotypic characteristics generally did not vary by skin cancer status. Hereditary retinoblastoma survivors have an increased risk for melanoma and NMSC that occurred earlier than that observed among nonhereditary survivors, likely reflecting genetic factors. These findings among White retinoblastoma survivors support consensus-based recommendations for skin cancer screening and sun protection starting at young ages and continuing long term.

CDKN2A genetic testing in melanoma-prone families in Sweden in the years 2015–2020: implications for novel national recommendations

Background: Inherited pathogenic variants (PVs) in the CDKN2A gene are among the strongest known risk factors for cutaneous melanoma. Carriers are at high risks to develop multiple primary melanomas and other cancers, in particular pancreatic cancer. In this study, the CDKN2A testing, carried out in Sweden in the years 2015–2020, was evaluated. Materials and methods: Included families had (1) three or more cases of melanoma and/or pancreatic cancer, (2) two melanomas in first-degree relatives, the youngest case <55 years or (3) individuals with three or more multiple primary melanomas, the first before the age of 55 years, and no other affected family members. The included families had at least one affected member that had been tested for CDKN2A PVs. Results: In total, 403 families were included, whereof 913 family members had been diagnosed with cutaneous melanoma and 129 with pancreatic cancer, 33 (8.2%) were found to have PVs in CDKN2A. Frequencies ranged from 0.9% in families with only two melanomas to 43.2% in families with three or more melanoma cases and pancreatic cancer (p < 0.001). The frequency of PVs ranged from 2.1% to 16.5% in families where the youngest case was ≥55 years or <35 years (p = 0.040). In families with or without CDKN2A PVs, 37.6% and 10.0% had melanoma cases that had died from melanoma, respectively (p < 0.001). Discussion: Significant differences were seen in the frequencies of CDKN2A PVs, dependent on numbers or age at diagnosis of melanomas and diagnoses of pancreatic cancers in the family. Further, melanoma cases belonging to families that tested positive for CDKN2A PVs had a significantly higher mortality. To summarize, the current evaluation shows that, with adequately selected criteria to guide genetic testing, CDKN2A PVs are identified at significant frequencies. Identification of carrier families is of importance to ensure that members are enrolled in a preventive surveillance program.

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families

BackgroundIndividuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited.MethodsIndividuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates.ResultsA total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis.ConclusionsAlthough sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

The Impact of Longitudinal Surveillance on Tumor Thickness for Melanoma-Prone Families with and without Pathogenic Germline Variants of CDKN2A and CDK4

Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking. We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries]. Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings (P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families. Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families. The study findings support the clinical benefit of screening (physician and self) for this high-risk population.

Constitutional variants in POT1, TERF2IP, and ACD genes in patients with melanoma in the Polish population.

Evaluation of the prevalence of POT1, ACD, and TERF2IP mutations among Polish melanoma patients. A cohort of 60 patients from melanoma-prone families, 1500 unselected cases and 1500 controls were genotyped. Methodology included Sanger sequencing, in-silico software predilection, and TaqMan assays. We identified three nonsynonymous variants: POT1 c.903 G>T; TERF2IP c.970 A>G; and ACD c.1544 T>C and a splice site variant ACD c.645 G>A. The c.903 G>T was predicted to be pathogenic according to PolyPhen-2, benign according to Mutation Taster, PROVEAN, AGVGD, and SIFT. The c.645 G>A was defined as disease caused by Mutation Taster and Human Splicing Finder and as variant of unknown significance by ClinVar. The other detected variants were described as benign. The c.903 G>T variant was present in two unselected cases and one control [P = 0.57, odds ratio (OR) = 2.00]; the c.645 G>A variant was not detected among the unselected cases and the controls; the c.970 A>G variant was present in 110 cases and 133 controls (P = 0.14, OR = 0.81); the c.1544 T>C variant was present in 687 cases and 642 controls (P = 0.11, OR = 1.07). We found no loss of heterozygosity of the c.903 G>T, c.970 A>G, and c.645 G>A variants. C.645 G>A variant had no effect on splicing or expression. The changes in POT1 c.903 G>T and ACD c.645 G>A can be classified as rare variants of unknown significance, the other variants appear to be polymorphisms. Germline mutations in POT1, ACD, and TERF2IP are infrequent among Polish melanoma patients.

The tumor genetics of acral melanoma: What should a dermatologist know?

Dermatologists stand at the gateway of individualization of classification, treatment, and outcomes of acral melanoma patients. The acral melanoma genetic landscape differs in vital ways from that of other cutaneous melanomas. These differences have important implications in understanding pathogenesis, treatment, and prognosis. The selection of molecularly targeted therapy must be adapted for acral melanoma. It is also critical to recognize that tumor development is far more complex than an isolated event, reliably treated by a medication acting on a single target. Tumors exhibit intratumor genetic heterogeneity, metastasis may have different genetic or epigenetic features than primary tumors, and tumor resistance may develop because of the activation of alternative genetic pathways. Microenvironmental, immune, and epigenetic events contribute and sustain tumors in complex ways. Treatment strategies with multiple targets are required to effectively disrupt the tumor ecosystem. This review attempts to translate the current molecular understanding of acral melanoma into digestible concepts relevant to the practice of dermatology. The focus is tumor genetics defining potentially treatable cancer pathways, contextualized within the relevant pathologic and molecular features.

A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer.

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

Priority of Risk (But Not Perceived Magnitude of Risk) Predicts Improved Sun-Protection Behavior Following Genetic Counseling for Familial Melanoma.

Understanding multiple components of risk perceptions is important because perceived risk predicts engagement in prevention behaviors. To examine how multiple components of risk perceptions (perceived magnitude of and worry about risk, prioritization of the management of one's risk) changed following genetic counseling with or without test reporting, and to examine which of these components prospectively predicted improvements in sun-protection behavior 1 year later. A prospective, nonrandomized study design was used. Participants were 114 unaffected members of melanoma-prone families who (i) underwent genetic testing for a CDKN2A/p16 mutation (n = 69) or (ii) were at comparably elevated risk based on family history and underwent genetic counseling but not testing (no-test controls, n = 45). Participants reported risk perception components and sun-protection behavior at baseline, immediately following counseling, and 1 month and 1 year after counseling. Factor analysis indicated three risk components. Carriers reported increased perceived magnitude and priority of risk, but not cancer worry. No-test controls showed no changes in any risk perception. Among noncarriers, priority of risk remained high at all assessments, whereas magnitude of risk and cancer worry decreased. Of the three risk components, greater priority of risk uniquely predicted improved self-reported sun protection 1 year post-counseling. Priority of risk (i) seems to be a component of risk perceptions distinguishable from magnitude of risk and cancer worry, (ii) may be an important predictor of daily prevention behavior, and (iii) remained elevated 1 year following genetic counseling only for participants who received a positive melanoma genetic test result.

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

CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. 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. 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. Limited sample sizes for rare melanoma-susceptibility syndromes (CDK4, POT1). Spitzoid morphology was associated with POT1 mutations suggesting that telomere dysfunction (POT1 mutations) may contribute to spitzoiddifferentiation in melanocytic tumors.

Clinical, pathological and dermoscopic phenotype of MITF p.E318K carrier cutaneous melanoma patients

BackgroundThe p.E318K variant of the Melanocyte Inducing Transcription Factor (MITF) has been implicated in genetic predisposition to melanoma as an intermediate penetrance allele. However, the impact of this variant on clinico-phenotypic, as well as on dermoscopic patterns features of affected patients is not entirely defined. The purpose of our study was to assess the association between the p.E318K germline variant and clinic-phenotypical features of MITF+ compared to non-carriers (MITF−), including dermoscopic findings of melanomas and dysplastic nevi.Methodswe retrospectively analyzed a consecutive series of 1386 patients recruited between 2000 and 2017 who underwent genetic testing for CDKN2A, CDK4, MC1R and MITF germline variants in our laboratory for diagnostic/research purposes. The patients were probands of melanoma-prone families and apparently sporadic single or multiple primary melanoma patients. For all, we collected clinical, pathological information and dermoscopic images of the histopathologically diagnosed melanomas and dysplastic nevi, when available.ResultsAfter excluding patients positive for CDKN2A/CDK4 pathogenic variants and those affected by non-cutaneous melanomas, our study cohort comprised 984 cutaneous melanoma patients, 22 MITF+ and 962 MITF−. MITF+ were more likely to develop dysplastic nevi and multiple primary melanomas. Nodular melanoma was more common in MITF+ patients (32% compared to 19% in MITF−). MITF+ patients showed more frequently dysplastic nevi and melanomas with uncommon dermoscopic patterns (unspecific), as opposed to MITF− patients, whose most prevalent pattern was the multicomponent.ConclusionsMITF+ patients tend to develop melanomas and dysplastic nevi with histopathological features, frequency and dermoscopic patterns often different from those prevalent in MITF− patients. Our results emphasize the importance of melanoma prevention programs for MITF+ patients, including dermatologic surveillance with digital follow-up.

Variation in Cutaneous Patterns of Melanomagenesis According to Germline CDKN2A/CDK4 Status in Melanoma-Prone Families

CDKN2A and CDK4 are well-established melanoma susceptibility genes, but their effect on tumor location and distribution is unknown. We used a case-case study design to assess for differences in tumor location between mutation carriers (CDKN2A= 141 patients, 348 melanomas; CDK4= 15 patients, 54 melanomas) and noncarriers (104 patients, 157 melanomas) in US melanoma-prone families. Associations between groups were assessed with chi-square tests. Odds ratios (ORs) for tumor location were adjusted for diagnosis age, gender, and superficial spreading subtype. Models included random effects to account for within individual and family correlations. Compared with having a truncal melanoma, CDK4 (vs. noncarriers: lower extremities OR= 14.5, 95% confidence interval [CI]= 5.02-42.0, P < 0.001; upper extremities OR= 6.88, 95% CI=2.37-19.9, P < 0.001; head and neck OR= 18.6, 95% CI= 4.04-85.2, P < 0.001) and CDKN2A (vs. noncarriers: lower extremities OR= 3.01, 95% CI= 1.56-5.82, P < 0.05; upper extremities OR= 1.91, 95% CI=1.03-3.52, P< 0.05; head and neck OR= 5.40, 95% CI= 2.10-13.9, P < 0.001) carriers had higher odds of developing melanoma at all other sites. Similar findings were observed for analyses stratified by gender, age, and first versus subsequent melanoma diagnoses. Further studies are needed to understand the biology underlying these genotype-associated patterns of tumor development, which could provide new insights into melanoma treatment and prevention.