Multiple Primary Melanomas Research Articles

Synchronous primary cutaneous melanomas: a descriptive study of their clinical features, histology, genetic background of the patients and clinical outcomes.

Around 0.5% of cutaneous melanoma (CM) patients will present with synchronous melanomas when first seen. Moreover, 26-40% of patients with multiple primary melanomas present with synchronous lesions. To assess the prevalence, clinical and histopathological characteristics, germline mutations and outcome in patients with synchronous melanoma. Clinical and histopathological data from 4703 melanoma patients were included. Clinical, histological and genetic mutational status information was analysed. Kaplan-Meier curves were used to investigate survival outcomes. A total of 144 patients (3.06%) presented simultaneously with two or more primary melanomas. During follow-up, 25.7% of patients with synchronous melanoma developed a new primary melanoma compared to 8.6% of patients diagnosed with single melanoma (P < 0.001). Germinal CDKN2A mutations were identified in 10.7% of patients with synchronous melanomas and genetic variants in MC1R in 72%. No significant differences in all survival outcomes between patients with synchronous melanomas and single melanomas were found. Synchronous melanomas are more frequent than previously reported and are more frequent in older patients compared to single melanomas. Moreover, these patients have a higher risk of developing a new primary melanoma during follow-up and have higher rates of germline susceptibility variants. Nevertheless, these findings were not associated with worse outcomes.

Multiple primary melanoma in association with other personal and familial cancers.

Multiple primary melanoma (MPM) is known to be associated with familial melanoma. However, the association between MPM and other personal and familial cancers is not well documented. The objective of this study was to evaluate the association between MPM and personal history of other cancers or cancer history among first-degree relatives (FDRs). We performed a retrospective case-control study including cases with gender-matched MPM and single primary melanoma (SPM) at a 1:2 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The associations between MPM and other cancers were evaluated using univariable and multivariable logistic regression models. In total, 378 patients (44.2% men; median age 52 years) were enrolled, including 252 with SPM and 126 with MPM. In comparison to patients with SPM, patients with MPM were more likely to have squamous cell carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.001-3.79, p=0.047) and prostate cancer (OR 2.72, 95% CI 1.07-7.01, p=0.034). FDRs of patients with MPM had higher prevalence of melanoma (OR 2.37, 95% CI 1.31-4.28, p=0.004) and prostate cancer (OR 2.92, 95% CI 1.47-6.14, p=0.002) but not other cancers. In multivariable analysis, the association remained significant between MPM and squamous cell carcinoma (OR 2.18, 95% CI 1.08-4.39, p=0.028), prostate cancer (OR 2.85, 95% CI 1.09-7.54, p=0.032), FDR history of melanoma (OR 2.37, 95% CI 1.31-4.29, p=0.004), and FDR history of prostate cancer (OR 3.26, 95% CI 1.59-6.83, p=0.001). Patients with MPM have a higher prevalence of personal and FDR histories of nonmelanoma skin cancers and prostate cancer.

186 Improved survival of multiple vs single primary melanomas

Background: Patients with single primary melanomas have an increased risk of developing subsequent melanomas. Second tumors diagnosed within three months of the incident lesion are termed “synchronous”, while “asynchronous” tumors are diagnosed outside of this window. Objective: Compare the tumor distributions and survival characteristics of patients with synchronous and asynchronous second primary melanomas to patients with single primary melanomas. Methods: Retrospective cohort study. Data were collected from an institutional database from 14,029 patients with a diagnosis of a primary melanoma seen between 1970 and 2004.

Germline predisposition in oncologic and dermatologic melanoma cohorts.

10523 Background: Melanoma has recently been suggested to be a highly heritable cancer with high twin-twin concordance. In contrast, prior studies on patients with familial atypical multiple mole melanoma (FAMMM) syndrome, multiple primary melanomas and early age of onset, all known to be associated with germline CDKN2A/CDK4 pathogenic variants, suggest that individuals with melanoma who carry germline alterations are rare. We studied the overall prevalence of germline cancer predisposition in a large prospective oncologic cohort with comparison to other defined cohorts of individuals with melanoma with available germline data. Methods: Individuals who presented to medical oncology clinic with a diagnosis of melanoma and personal or family history of multiple cancers were offered germline testing with a commercially available next generation sequencing panel (Invitae, San Francisco, CA). Eligibility criteria required ≥ 2 melanomas in an individual or family; melanoma and other cancer(s) in an individual; melanoma and at least 2 other cancers in 1st- or 2nd-degree relatives; age ≤35 at diagnosis; or limited family structure. Comparative analysis of germline NGS data from 3 additional selected and non-selected melanoma datasets was performed. Results: In a cohort of 400 oncology patients with melanoma who consented to commercial germline testing of 85 cancer-associated genes, a germline pathogenic/likely pathogenic (gP/LP) positive rate of 15.3% (n = 61) was observed. Genes previously associated with inherited melanoma ( BAP1, BRCA1/2, CDKN2A, MITF, TP53) comprised less than one-third of gP/LP variants (20, 32.7%); the majority of germline variants were in cancer predisposition genes not traditionally associated with melanoma (e.g. BRIP1, CHEK2, MSH2, PMS2, MLH1, RAD51C, BLM). Family history of non-cutaneous cancer (42, 69%) and personal history of melanoma with ≥ 1 non-cutaneous cancer (22, 36%) were the most common eligibility criteria met in gP/LP variant carriers. Analysis of germline data from other large oncologic and dermatologic melanoma datasets yielded gP/LP variant positive rates of 10.6% in an unselected oncologic melanoma cohort (TCGA, n = 470), 15.8% in a selected commercial testing cohort (Invitae, n = 12,571), and 14.5% in a highly selected, primarily dermatologic subset (Boston-Athens, n = 289). Conclusions: In oncologic and dermatologic cohorts, germline testing of selected individuals with melanoma yields rates of clinically impactful P/LP variant detection which exceed consensus standards for pretest probability. Most P/LP variants were found in genes associated with non-cutaneous cancers. Obtaining a family and personal history of cancer, particularly non-cutaneous cancers, and referring for broad panel-based germline testing in all individuals with melanoma are recommended.

Sensitivity of two Australian melanoma risk tools to identify high-risk individuals among people presenting with their first primary melanoma.

Regular skin examinations for early detection of melanoma are recommended for high-risk individuals, but there is minimal consensus regarding what constitutes 'high-risk'. Melanoma risk prediction models may guide this. We compared two online melanoma risk prediction tools: Victorian Melanoma Service (VMS) and Melanoma Institute Australia (MIA) risk tools; to assess classification differences of patients at high-risk of a first primary melanoma. Risk factor data for 357 patients presenting with their first primary melanoma were entered into both risk tools. Predicted risks were recorded: 5-year absolute risk (VMS tool and MIA tool); 10-year, lifetime, and relative risk estimates (MIA tool). Sensitivities for each tool were calculated using the same high-risk thresholds. The MIA risk tool showed greater sensitivity on comparison of 5-year absolute risks (90% MIA vs 78% VMS). Patients had significantly higher odds of being classified as high or very-high risk using the MIA risk tool overall, and for each patient subgroup. Using either tool, patients of male gender or with synchronous multiple first primary melanomas were more likely to be correctly classified as high- or very-high risk using 5-year absolute risk thresholds; but tumour invasiveness was unrelated to risk. Classification differed when using the MIA risk categories based on relative risk. Both melanoma risk prediction tools had high sensitivity for identifying individuals at high-risk and could be used for optimising prevention campaigns. The choice of which risk tool, measure, and threshold for risk stratification depends on the intended purpose of risk prediction, and ideally requires information on specificity.

Multiple Primary Melanomas: Retrospective Review in a Tertiary Care Hospital.

Multiple primary melanomas (MPM) refer to the occurrence of more than one synchronous or metachronous melanoma in the same individual. The aim of this study was to identify the frequency of MPM and describe the clinical and histopathologic characteristics of patients with MPM. An observational single-center retrospective study was designed based on a cohort of melanoma patients followed in a tertiary care hospital. Fifty-eight (8.9%) patients developed MPM. Most patients were men (65.5%) and the median age at the time of diagnosis of the first melanoma was 71 years old. The median time of diagnosis of the second melanoma from the first melanoma was 10.9 months, and 77.6% of second melanomas were diagnosed within the first 5 years. In total, 29 (50%) and 28 (48.3%) first and second melanomas were located in the trunk, respectively. Concordance of anatomic site between primary and subsequent melanoma was found in 46.6% of the patients. Proportion of in situ melanomas was increasingly higher in subsequent melanomas (from 36.21% of first melanomas to 100% of fifth melanomas). An increasing rate of melanomas with histological regression was observed within subsequent melanomas (from 60.3% of first melanomas to 80% of third melanomas). Our results support the importance of careful long-term follow-up with total body examination in melanoma patients.

Poorer survival outcomes in patients with multiple versus single primary melanoma.

Given equivocal results related to overall survival (OS) for patients with multiple primary melanomas (MPMs) compared with those with single primary melanomas (SPMs) in previous reports, the authors sought to determine whether OS differs between these 2 cohorts in their center using their UPCI-96-99 database. Secondary aims were to assess the differences in recurrence-free survival (RFS). In a subset of patients, transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) was performed to assess disease-associated genes of interest. This retrospective case-controlled study included patients with MPMs and age-, sex-, and stage-matched controls with SPMs at a 1:1 ratio. Cox regression models were used to evaluate the effect of the presence of MPMs on death and recurrence. NanoString PanCancer Immune Profiling was used to assess peripheral blood immune status in patients. In total, 320 patients were evaluated. The mean patient age was 47years; 43.8% were male. Patients with MPMs had worse RFS and OS (P=.023 and P=.0019, respectively). The presence of MPMs was associated with an increased risk of death (hazard ratio [HR], 4.52, P=.0006), and increased risk of disease recurrence (HR, 2.17; P=.004) after adjusting for age, sex, and stage. The degree of tumor-infiltrating lymphocytes (TILs) was different between the first melanoma of MPMs and SPMs. Expression of CXCL6 and FOXJ1 was increased in PBMCs isolated from patients with MPMs. Patients with MPMs had worse RFS and OS compared with patients with SPMs. Immunologic differences were also observed, including TIL content and expression of CXCL6/FOXJ1 in PBMCs of patients with MPMs, which warrant further investigation.

CDKN2A-positive melanoma patient treated with combination immunotherapy – A case report

Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia

PurposeAtaxia–Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. MethodsFrom 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. ResultsLOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56–4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6–5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case–control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). ConclusionThis study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Lack of association between CDKN2A germline mutations and survival in patients with melanoma: A retrospective cohort study

Lack of association between CDKN2A germline mutations and survival in patients with melanoma: A retrospective cohort study

1330Is Prognosis Worse for People with Multiple Versus Single Primary Melanoma?

Abstract Background Patients with a primary melanoma may develop more than one in their lifetime. It is unclear whether mortality is worse after diagnosis of multiple primary melanoma (MPM) compared with single primary melanoma (SPM). Methods We analysed data from a population-based cohort of 3,869 patients diagnosed with primary in situ or invasive cutaneous melanoma in New South Wales, Australia in 2006-07 and followed up until 2018 (median 11.9 years) using linked mortality and cancer registry data. We compared overall mortality and melanoma-specific mortality for patients with SPM versus MPM, adjusting for other clinico-pathological prognostic indicators, using Cox proportional hazard models. The primary analysis was based on pathological features from the thickest tumour for MPM patients, however sensitivity analyses were performed using the first and last primary melanoma. Results The cohort consisted of 3,869 patients (2,929 SPM and 940 MPM) and 5,504 melanoma lesions (including 2,575 lesions from MPM patients). The primary multivariable analysis showed MPM was associated with lower mortality from all causes and melanoma compared with SPM with a hazard ratio of 0.62 (95% CI: 0.54-0.71, p &amp;lt; 0.001) and 0.37 (95% CI: 0.32-0.43, p &amp;lt; 0.001) respectively. These findings were also supported by the sensitivity analyses. Conclusions The diagnosis of MPM does not worsen mortality compared to a SPM, in fact it was associated with improved survival. This finding might be related to skin examination behaviours, biological or clinical factors. Key messages MPM patients have a better prognosis than SPM patients.

Familial Melanoma and Susceptibility Genes: A Review of the Most Common Clinical and Dermoscopic Phenotypic Aspect, Associated Malignancies and Practical Tips for Management.

A family history of melanoma greatly increases the risk of developing cutaneous melanoma, a highly aggressive skin cancer whose incidence has been steadily increasing worldwide. Familial melanomas account for about 10% of all malignant melanomas and display an inheritance pattern consistent with the presence of pathogenic germline mutations, among which those involving CDKN2A are the best characterized. In recent years, a growing number of genes, such as MC1R, MITF, CDK4, POT1, TERT, ACD, TERF2IP, and BAP1, have been implicated in familial melanoma. The fact that individuals harboring these germline mutations along with their close blood relatives have a higher risk of developing multiple primary melanomas as well as other internal organ malignancies, especially pancreatic cancer, makes cascade genetic testing and surveillance of these families of the utmost importance. Unfortunately, due to a polygenic inheritance mechanism involving multiple low-risk alleles, genetic modifiers, and environmental factors, it is still very difficult to predict the presence of these mutations. It is, however, known that germline mutation carriers can sometimes develop specific clinical traits, such as high atypical nevus counts and specific dermoscopic features, which could theoretically help clinicians predict the presence of these mutations in prone families. In this review, we provide a comprehensive overview of the high- and intermediate-penetrance genes primarily linked to familial melanoma, highlighting their most frequently associated non-cutaneous malignancies and clinical/dermoscopic phenotypes.

Identification of death risk factors of primary melanoma based on the competing risk model

To preliminarily explore death risk factors in primary melanoma patients. Competing risk model analysis was used using a large sample public cohort and Cox proportional hazard model was compared. In the competing risk model analysis, age, gender, ethnicity, stage, site, TMN stage and metastases were the independent risk factors of single primary melanoma (SPM) death. T stage had a particularly important impact on SPM death. T2 stage had a 3.212 times greater risk of interest event than T1 stage [hazard ratio (HR)=3.212, 95%CI: 2.994-3.446], T3 stage was 5.747 times greater than that T1 stage (HR=5.747, 95%CI: 5.337-6.187) and T4 stage had a 7.086 times than T1 stage (HR=7.086, 95%CI: 6.514-7.708). Gender, ethnicity, stage, site, T stage and brain and liver metastases were the independent risk factors of multiple primary melanoma (MPM) death. When some groups had a very high death rate or the reference group had a very low death rate in competing events, the results of Cox proportional hazard model may not be as accurate as the results obtained by fine-Gray regression model. Early diagnosis and therapy, and prevention of tumor progression and metastases of primary melanoma patients are important measures to improve its prognosis and survival.

Increased melanoma recurrence in patients with multiple primary invasive melanomas

To the Editor: Primary melanoma patients have an increased risk of developing other primary melanomas over time, but the influence of multiple primary melanomas on recurrence rates is unknown. Survival was formerly believed to be better in those with multiple primary melanomas,1 but it is now known to be worse with increased melanoma mortality.2 We prospectively assessed the recurrence rates in patients 5 years after the diagnosis of high-risk primary melanoma, comparing patients in whom other primary melanomas developed before or since their index primary melanoma with patients with only the index melanoma.

Incidence of Synchronous Multiple Primary Melanoma in Patients with Solitary Melanoma: a Prospective Comparative Study

Background. Malignant melanoma is steadily exaggerating over the recent decades. Nonetheless, improved systemic therapies have substantially increased life expectancy in patients with a locally advanced or disseminated disease. Higherincidence recurrent melanocytic skin lesions become essentially problematic and require more attention and control.Aim. Cross-survey on the incidence of synchronous multiple primary melanomas in patients with solitary melanoma and those with other operable solid tumours.Materials and methods. A total of 289 patients with suspected malignant pigmented skin melanoma were included in the survey. Patients were divided in two cohorts by the presence of primary skin melanoma and its tractability for radical excision. Patients with operable melanoma comprised the study cohort, and those with other solid tumours were the control.Results and discussion. The survey covered 289 patients, with 148 in the study and 141 in the control cohort. The study148 patients revealed 112 malignant pigmented melanomas, but none in the control cohort. A chi-square statistical analysis of clinical values in single and multiple melanoma cases showed a slightly higher prevalence of first-visit melanomas in patients with synchronous tumours (30% pT4 — p = 0.007).Conclusion. The observed 10% rate of second melanoma in the study cohort and a zero melanoma incidence in the control support the alternative hypothesis of a higher rate of newly detected melanomas in primarily diagnosed melanoma patients vs. those with solid tumours.

Transcriptomic profiling of peripheral blood mononuclear cells in patients with multiple primary melanoma.

e21558 Background: Patients (PTs) with cutaneous melanoma (MEL) are at increased risk of developing subsequent MEL. The primary objective of the present study was to determine whether the peripheral blood gene expression profile (GEP) of PTs with multiple primary melanoma (MPM) differs from that of patients with single primary melanoma (SPM) and healthy controls (HCs). A secondary objective is to assess if the peripheral blood immune transcriptional profile varies in relation with clinical and immunopathological characteristics of MEL. Methods: Cases with MPM, SPM and HCs were retrieved from the University of Pittsburgh Human Biological Sample and Nevus Image Banking and Analysis Repository. NanoString PanCancer Immune Profiling of 770-immune related genes was used to define GEP in peripheral blood mononuclear cells (PBMCs). Quality control (QC), data normalization, and differential expression analyses were performed using the ROSALIND Analysis System. Genes with fold change ≥1.5 and p-value &lt; 0.05 were considered as differentially-expressed between cohorts. Results: In total, 47 PTs including 10 with SPM, 40 with MPM, and 10 HCs, were included. GEP data from 3 cases did not meet QC requirements and were discarded. The majority of PTs had stage I/II disease (87.2%). The median Breslow thickness was 1 mm, ulceration was present in 6 (12.2%) MELs. Tumor-infiltrating lymphocytes (TILs) were absent, non-brisk, and brisk in 20%, 65%, 15% of cases, respectively. The expression of IFIT1, MX1, ISG15 was decreased in PTs with MPM in comparison to HCs. In comparison to SPMs, PTs with MPM demonstrated downregulation of B-cell receptor signaling pathway genes (CD19, CD22, CD79A, BLK). 14 genes involved in TNF-alpha effects on cytokine activity, cell motility, and apoptosis, and 12 genes in the IL18 signaling pathway were differentially expressed in PTs with Breslow thickness of &gt;1mm vs ≤1mm. The top downregulated genes in &gt;1mm thick MELs were CD83, VEGFA and CXCL3. Ulcerated MEL had decreased expression of CCL2, CCL3, CCL3L1, CCL4. Stage III MEL had decreased expression of GZMH, MHC Class II genes HLA-DMB, HLA-DRB3, lectin receptor family genes KLRC2 and KLRD1, as well as Type-1 immune-associated biomarkers IRF1, SYK, TBX21 in comparison to Stage I/II cases. Tumors deficient in TILs exhibited decreased expression of Granzyme A and B, T-box 21, and IL18RAP (enhances IL18R-mediated signaling) in peripheral blood. Tumors with brisk TILs had increased expression of the B-cell associated transcripts CD19, CD22, CD79A in peripheral blood. Conclusions: The GEP of PBMC's from PTs with MPM was similar overall to that of PTs with SPM/HC, with only a subset of genes exhibiting differentially expression in PTs with MPM vs. PTs with SPM and HCs. GEP varied in relation to Breslow thickness, stage, ulceration, and TIL content in MELs.

Multiple primary melanoma in association with other personal and family history of cancers.

e21559 Background: Patients (PTs) with cutaneous melanoma are at increased risk of developing second primary melanoma and non-melanoma skin cancers. The primary aim of this study was to define the association between MPM and personal history of non-melanoma skin cancers and other non-skin cancers. The secondary aim was to evaluate the association between MPM and the presence of other cancers among first-degree relatives (FDRs). Methods: We performed a retrospective case-control study including cases with MPM and controls with single primary melanoma (SPM) from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The proportions and percentages of non-melanoma skin cancer, other non-skin cancer, 1st degree family history of melanoma, and 1st degree family history of other non-melanoma cancers were calculated separately for MPM and SPM groups. Fisher’s exact tests were performed to test whether MPM was associated with these variables. For each significant variable, a multivariable logistic regression model was used to test its association with MPM after adjusting for age, gender, melanoma staging, and smoking status. Results: In total, 311 PTs (39.2% men; median age at initial diagnosis 51years) were enrolled, including 194 with SPM (38.6%; 51) and 117 with MPM (39.8%; 48). 28 (9%) of PTs had squamous cell carcinoma (SCC), and 63 (20%) had basal cell carcinoma (BCC). The most common non-skin cancers in the whole cohort were prostate (4.8%), breast (3.8%), hematological (1.9%), colorectal (1.3%), and cervical cancers (1.3%). FDR history of melanoma, non-melanoma skin cancer, and other cancers were positive in 15.4%, 7.1% and 46.3% PTs, respectively. The most common non-skin cancers in FDRs were breast, prostate, lung, colorectal and hematological malignancies. In comparison to PTs with SPM, PTs with MPM were more likely to have SCC (14.5% vs 5.7%, p=0.013) but not BCC and other non-skin cancers. FDRs of PTs with MPM had higher prevalence of melanoma (23.1% vs 10.8%, p=0.005), prostate cancer (31.9% vs 5.3%, p=0.0002) but not other non-melanoma skin and non-skin cancers. In multivariate analysis the association remained significant between MPM and SCC (OR 2.7, 95% CI 1.1-6.6, p=0.032), FDR history of melanoma (OR 2.0, 95% CI 1.03-4.1, p=0.042), and FDR history of prostate cancer (OR 5.6, 95% CI 1.6-20.3, p=0.008). Conclusions: MPM is associated with higher prevalence of SCC and FDR history of melanoma and prostate cancer, but not BCC and other non-melanoma cancers in comparison to SPM.

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.

Unraveling the role of microRNA/isomiR network in multiple primary melanoma pathogenesis

Malignant cutaneous melanoma (CM) is a potentially lethal form of skin cancer whose worldwide incidence has been constantly increasing over the past decades. During their lifetime, about 8% of CM patients will develop multiple primary melanomas (MPMs), usually at a young age and within 3 years from the first tumor/diagnosis. With the aim of improving our knowledge on MPM biology and pathogenesis, we explored the miRNome of 24 single and multiple primary melanomas, including multiple tumors from the same patient, using a small RNA-sequencing approach. From a supervised analysis, 22 miRNAs were differentially expressed in MPM compared to single CM, including key miRNAs involved in epithelial–mesenchymal transition. The first and second melanoma from the same patient presented a different miRNA profile. Ten miRNAs, including miR-25-3p, 149-5p, 92b-3p, 211-5p, 125a-5p, 125b-5p, 205-5p, 200b-3p, 21-5p, and 146a-5p, were further validated in 47 single and multiple melanoma samples. Pathway enrichment analysis of miRNA target genes revealed a more differentiated and less invasive status of MPMs compared to CMs. Bioinformatic analyses at the miRNA isoform (isomiR) level detected a panel of highly expressed isomiRs belonging to miRNA families implicated in human tumorigenesis, including miR-200, miR-30, and miR-10 family. Moreover, we identified hsa-miR-125a-5p|0|−2 isoform as tenfold over-represented in melanoma than the canonical form and differentially expressed in MPMs arising in the same patient. Target prediction analysis revealed that the miRNA shortening could change the pattern of target gene regulation, specifically in genes implicated in cell adhesion and neuronal differentiation. Overall, we provided a putative and comprehensive characterization of the miRNA/isomiR regulatory network of MPMs, highlighting mechanisms of tumor development and molecular features differentiating this subtype from single melanomas.

Efficiency of Detecting New Primary Melanoma Among Individuals Treated in a High-risk Clinic for Skin Surveillance

A previous single-center study observed fewer excisions, lower health care costs, thinner melanomas, and better quality of life when surveillance of high-risk patients was conducted in a melanoma dermatology clinic with a structured surveillance protocol involving full-body examinations every 6 months aided by total-body photography (TBP) and sequential digital dermoscopy imaging (SDDI). To examine longer-term sustainability and expansion of the surveillance program to numerous practices, including a primary care skin cancer clinic setting. This prospective cohort study recruited 593 participants assessed from 2012 to 2018 as having very high risk of melanoma, with a median of 2.9 years of follow-up (interquartile range, 1.9-3.3 years), from 4 melanoma high-risk clinics (3 dermatology clinics and 1 primary care skin cancer clinic) in New South Wales, Australia. Data analyses were conducted from February to September 2020. Six-month full-body examination with the aid of TBP and SDDI. For equivocal lesions, the clinician performed SDDI at 3 or 6 months. All suspect monitored or excised lesions were recorded, and pathology reports obtained. Outcomes included the incidence and characteristics of new lesions and the association of diagnostic aids with rates of new melanoma detection. Among 593 participants, 340 (57.3%) were men, and the median age at baseline was 58 years (interquartile range, 47-66 years). There were 1513 lesions excised during follow-up, including 171 primary melanomas. The overall benign to malignant excision ratio, including keratinocyte carcinomas, was 0.8:1.0; the benign melanocytic to melanoma excision ratio was 2.4:1.0; and the melanoma in situ to invasive melanoma ratio was 2.2:1.0. The excision ratios were similar across the 4 centers. The risk of developing a new melanoma was 9.0% annually in the first 2 years and increased with time, particularly for those with multiple primary melanomas. The thicker melanomas (>1-mm Breslow thickness; 7 of 171 melanomas [4.1%]) were mostly desmoplastic or nodular (4 of 7), self-detected (2 of 7), or clinician detected without the aid of TBP (3 of 7). Overall, new melanomas were most likely to be detected by a clinician with the aid of TBP (54 of 171 [31.6%]) followed by digital dermoscopy monitoring (50 of 171 [29.2%]). The structured surveillance program for high-risk patients may be implemented at a larger scale given the present cohort study findings suggesting the sustainability and replication of results in numerous settings, including a primary care skin cancer clinic.