Publications by authors named "Paola Ghiorzo"

97 Publications

Melanoma In Children And Adolescents: Analysis Of Susceptibility Genes In 123 Italian Patients.

J Eur Acad Dermatol Venereol 2021 Oct 18. Epub 2021 Oct 18.

Dermatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.

Background: A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for pediatric patients.

Objective: We aim to analyze the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicenter cohort of Italian children and adolescents, in order to explore the genetic context of pediatric melanoma and to reveal potential differences in heritability between children and adolescents METHODS: One-hundred-twenty-three patients (<21 years) from nine italian centers were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated.

Results: Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients, and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, unfrequent red hair color, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤ 12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi.

Conclusion: Our results confirm the scarce involvement of the major high-risk susceptibility genes in pediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.
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http://dx.doi.org/10.1111/jdv.17735DOI Listing
October 2021

Insights into Mechanisms of Tumorigenesis in Neuroendocrine Neoplasms.

Int J Mol Sci 2021 Sep 25;22(19). Epub 2021 Sep 25.

Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.

Genomic studies have identified some of the most relevant genetic players in Neuroendocrine Neoplasm (NEN) tumorigenesis. However, we are still far from being able to draw a model that encompasses their heterogeneity, elucidates the different biological effects consequent to the identified molecular events, or incorporates extensive knowledge of molecular biomarkers and therapeutic targets. Here, we reviewed recent insights in NEN tumorigenesis from selected basic research studies on animal models, highlighting novel players in the intergenic cooperation and peculiar mechanisms including splicing dysregulation, chromatin stability, or cell dedifferentiation. Furthermore, models of tumorigenesis based on composite interactions other than a linear progression of events are proposed, exemplified by the involvement in NEN tumorigenesis of genes regulating complex functions, such as or . Although limited by interspecies differences, animal models have proved helpful for the more in-depth study of every facet of tumorigenesis, showing that the identification of driver mutations is only one of the many necessary steps and that other mechanisms are worth investigating.
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http://dx.doi.org/10.3390/ijms221910328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508699PMC
September 2021

Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1.

Hum Mol Genet 2021 Oct 4. Epub 2021 Oct 4.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples 80136, Italy.

The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.
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http://dx.doi.org/10.1093/hmg/ddab293DOI Listing
October 2021

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

Fam Cancer 2021 Jul 3. Epub 2021 Jul 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA.

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.
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http://dx.doi.org/10.1007/s10689-021-00267-9DOI Listing
July 2021

First international workshop of the ATM and cancer risk group (4-5 December 2019).

Fam Cancer 2021 Jun 14. Epub 2021 Jun 14.

Huntsman Cancer Institute, Salt Lake City, USA.

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.
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http://dx.doi.org/10.1007/s10689-021-00248-yDOI Listing
June 2021

Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, 16132 Genoa, Italy.

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/-MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/-MEKi with an expected rate derived from phase III trials and "real-world" studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (-value = 0.143; 95% CI = 0.60-0.97); the difference was statistically significant (-value = 0.019; 95% CI = 0.62-0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/-MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.
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http://dx.doi.org/10.3390/cancers13102440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157545PMC
May 2021

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

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Individuals 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.

Methods: Individuals 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.

Results: A 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.

Conclusions: Although 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.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

Quality assessment of a clinical next-generation sequencing melanoma panel within the Italian Melanoma Intergroup (IMI).

Diagn Pathol 2020 Dec 14;15(1):143. Epub 2020 Dec 14.

Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy.

Background: Identification of somatic mutations in key oncogenes in melanoma is important to lead the effective and efficient use of personalized anticancer treatment. Conventional methods focus on few genes per run and, therefore, are unable to screen for multiple genes simultaneously. The use of Next-Generation Sequencing (NGS) technologies enables sequencing of multiple cancer-driving genes in a single assay, with reduced costs and DNA quantity needed and increased mutation detection sensitivity.

Methods: We designed a customized IMI somatic gene panel for targeted sequencing of actionable melanoma mutations; this panel was tested on three different NGS platforms using 11 metastatic melanoma tissue samples in blinded manner between two EMQN quality certificated laboratory.

Results: The detection limit of our assay was set-up to a Variant Allele Frequency (VAF) of 10% with a coverage of at least 200x. All somatic variants detected by all NGS platforms with a VAF ≥ 10%, were also validated by an independent method. The IMI panel achieved a very good concordance among the three NGS platforms.

Conclusion: This study demonstrated that, using the main sequencing platforms currently available in the diagnostic setting, the IMI panel can be adopted among different centers providing comparable results.
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http://dx.doi.org/10.1186/s13000-020-01052-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737361PMC
December 2020

MC1R variants and cutaneous melanoma risk according to histological type, body site, and Breslow thickness: a pooled analysis from the M-SKIP project.

Melanoma Res 2020 10;30(5):500-510

Departments of Dermatology.

Little is known on whether melanocortin 1 receptor (MC1R) associated cutaneous melanoma (CM) risk varies depending on histological subtype and body site, and whether tumour thickness at diagnosis (the most important prognostic factor for CM patients) differs between MC1R variant carriers and wild-type individuals. We studied the association between MC1R variants and CM risk by histological subtype, body site, and Breslow thickness, using the database of the M-SKIP project. We pooled individual data from 15 case-control studies conducted during 2005-2015 in Europe and the USA. Study-specific, multi-adjusted odds ratios were pooled into summary odds ratios (SOR) and 95% confidence intervals (CI) using random-effects models. Six thousand eight hundred ninety-one CM cases and 5555 controls were included. CM risk was increased among MC1R variant carriers vs. wild-type individuals. The increase in risk was comparable across histological subtypes (SOR for any variant vs. wild-type ranged between 1.57 and 1.70, always statistical significant) except acral lentiginous melanoma (ALM), for which no association emerged; and slightly greater on chronically (1.74, 95% CI 1.47-2.07) than intermittently (1.55, 95% CI 1.34-1.78) sun-exposed skin. CM risk was greater for those carrying 'R' vs. 'r' variants; correlated with the number of variants; and was more evident among individuals not showing the red hair colour phenotype. Breslow thickness was not associated with MC1R status. MC1R variants were associated with an increased risk of CM of any histological subtype (except ALM) and occurring on both chronically and intermittently sun-exposed skin.
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http://dx.doi.org/10.1097/CMR.0000000000000668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479262PMC
October 2020

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications.

Front Mol Biosci 2020 24;7:172. Epub 2020 Jul 24.

Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy.

Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non- skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the genes (mostly ) and 70% showed mutations outside of the genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.
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http://dx.doi.org/10.3389/fmolb.2020.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396525PMC
July 2020

Current State of Target Treatment in BRAF Mutated Melanoma.

Front Mol Biosci 2020 14;7:154. Epub 2020 Jul 14.

Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Incidence of melanoma has been constantly growing during the last decades. Although most of the new diagnoses are represented by thin melanomas, the number of melanoma-related deaths in 2018 was 60,712 worldwide (Global Cancer Observatory, 2019). Until 2011, no systemic therapy showed to improve survival in patients with advanced or metastatic melanoma. At that time, standard of care was chemotherapy, with very limited results. The identification of V600 mutation, and the subsequent introduction of targeting drugs, radically changed the clinical practice and dramatically improved outcomes. In this review, we will retrace the development of molecular-target drugs and the current therapeutic scenario for patients with mutated melanoma, from the introduction of inhibitors as single agents to modern clinical practice. We will also discuss the resistance mechanisms identified so far, and the future therapeutic perspectives in mutated melanoma.
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http://dx.doi.org/10.3389/fmolb.2020.00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371970PMC
July 2020

Reply to E. Hindié.

J Clin Oncol 2020 09 23;38(27):3238-3240. Epub 2020 Jul 23.

Andrea Maurichi, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Rosalba Miceli, PhD, Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Hanna Eriksson, MD, PhD, Department of Oncology, Theme Cancer, Karolinska University Hospital, and Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Julia Newton-Bishop, MD, FRCP; Jérémie Nsengimana, PhD; and May Chan, PGD, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom; Andrew J. Hayes, MA, MBBS, MD, PhD and Kara Heelan, MB, BCH, BAO, MRCPI, MD, Sarcoma and Melanoma Units and Skin Unit, The Royal Marsden National Health Service (NHS) Foundation Trust, London, United Kingdom; David Adams, PhD, Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom; Roberto Patuzzo, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Francesco Barretta, MS, PhD, Medical Statistics, Biometry and Bioinformatics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Gianfranco Gallino, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Catherine Harwood, MA, MD, PhD, FRCP and Daniele Bergamaschi, PhD, Queen Mary University of London, London, United Kingdom; Dorothy Bennett, FMedSci, PhD, Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom; Konstantinos Lasithiotakis, MD, PhD, York Teaching Hospital NHS Foundation Trust, York, United Kingdom and Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Paola Ghiorzo, MD, PhD and Bruna Dalmasso, MD, University Hospital of Genoa, Genoa, Italy; Ausilia Manganoni, MD and Francesca Consoli, MD, University Hospital of Brescia, Brescia, Italy; Ilaria Mattavelli, MD; Consuelo Barbieri, MD; and Andrea Leva, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Umberto Cortinovis, MD, Plastic and Reconstructive Surgical Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Vittoria Espeli, MD and Cristina Mangas, MD, PhD, Istituto Oncologico Svizzera Italiana, Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland; Pietro Quaglino, MD; Simone Ribero, MD, PhD; and Paolo Broganelli, MD, University Hospital of Turin, Turin, Italy; Giovanni Pellacani, MD, University Hospital of Modena, Modena, Italy; Caterina Longo, MD, Arcispedale S. Maria Nuova, Reggio Emilia, Italy; Corrado Del Forno, MD, University Hospital of Pavia, Pavia, Italy; Lorenzo Borgognoni, MD and Serena Sestini, MD, Ospedale S. Maria Annunziata, Tuscan Cancer Institute, Florence, Italy; Nicola Pimpinelli, MD, PhD and Sara Fortunato, MD, Division of Dermatology, University of Florence, Florence, Italy; Alessandra Chiarugi, MD and Paolo Nardini, MD, Institute for Cancer Research and Prevention, Florence, Italy; Elena Morittu, PhD and Antonio Florita, PhD, Scientific Director's Office, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Mara Cossa, MD, PhD; Barbara Valeri, MD; Massimo Milione, MD, PhD; and Giancarlo Pruneri, MD, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; Odysseas Zoras, MD, PhD, University Hospital of Heraklion, Heraklion, Greece; Andrea Anichini, PhD and Roberta Mortarini, PhD, Immunobiology of Human Cancers Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy; and Mario Santinami, MD, Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

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http://dx.doi.org/10.1200/JCO.20.01460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499609PMC
September 2020

The Current State of Molecular Testing in the BRAF-Mutated Melanoma Landscape.

Front Mol Biosci 2020 30;7:113. Epub 2020 Jun 30.

Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

The incidence of melanoma, among the most lethal cancers, is widespread and increasing. Metastatic melanoma has a poor prognosis, representing about 90% of skin cancer mortality. The increased knowledge of tumor biology and the greater understanding of the immune system role in the anti-tumor response has allowed us to develop a more rational approach to systemic therapies. The discovery of activating mutations in half of all melanomas has led to the development of molecularly targeted therapy with BRAF and MEK inhibitors, which dramatically improved outcomes of patients with stage IV BRAF-mutant melanoma. More recently, the results of clinical phase III studies conducted in the adjuvant setting led to the combined administration of BRAF and MEK inhibitors also in patients with resected high-risk melanoma (stage III). Therefore, mutation testing has become a priority to determine the oncologist's choice and course of therapy. In this review, we will report the molecular biology-based strategies used for mutation detection with the main advantages and disadvantages of the most commonly used diagnostic strategies. The timing of such molecular assessment in patients with cutaneous melanoma will be discussed, and we will also examine considerations and approaches for accurate and effective testing.
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http://dx.doi.org/10.3389/fmolb.2020.00113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338720PMC
June 2020

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

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

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) 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.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Insights into Genetic Susceptibility to Melanoma by Gene Panel Testing: Potential Pathogenic Variants in ACD, and .

Cancers (Basel) 2020 04 19;12(4). Epub 2020 Apr 19.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, MD 20892, USA.

The contribution of recently established or candidate susceptibility genes to melanoma missing heritability has yet to be determined. Multigene panel testing could increase diagnostic yield and better define the role of candidate genes. We characterized 273 and negative probands through a custom-designed targeted gene panel that included and Co-segregation, loss of heterozygosity (LOH)/protein expression analysis, and splicing characterization were performed to improve variant classification. We identified 16 (5.9%) pathogenic and likely pathogenic variants in established high/medium penetrance cutaneous melanoma susceptibility genes ( and ), including two novel variants in and 4 in . We also found four deleterious and five likely deleterious variants in (3.3%). Thus, including potentially deleterious variants in increased the diagnostic yield to about 9%. Inclusion of rare variants of uncertain significance would increase the overall detection yield to 14%. At least 10% of melanoma missing heritability may be explained through panel testing in our population. To our knowledge, this is the highest frequency of putative deleterious variants reported in melanoma families, suggesting a possible role in melanoma susceptibility, which needs further investigation.
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http://dx.doi.org/10.3390/cancers12041007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226507PMC
April 2020

Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram.

J Clin Oncol 2020 05 13;38(14):1591-1601. Epub 2020 Mar 13.

University Hospital of Modena, Modena, Italy.

Purpose: Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB.

Patients And Methods: The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram.

Results: Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines.

Conclusion: We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.
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http://dx.doi.org/10.1200/JCO.19.01902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213590PMC
May 2020

Evolution of approaches to identify melanoma missing heritability.

Expert Rev Mol Diagn 2020 05 14;20(5):523-531. Epub 2020 Mar 14.

Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy.

: Around 10% of melanoma patients have a positive family history of melanoma and/or related cancers. Although a germline pathogenic variant in a high-risk gene can be identified in up to 40% of these patients, the remaining part of melanoma heritability remains largely unexplained.: The aim of this review is to provide an overview of the impact that new technologies and new research approaches had and are having on finding more efficient ways to unravel the missing heritability in melanoma.: High-throughput sequencing technologies have been crucial in increasing the number of genes/loci that might be implicated in melanoma predisposition. However, results from these approaches may have been inferior to the expectations, due to an increase in quantitative information which hasn't been followed at the same speed by an improvement of the methods to correctly interpret these data. Optimal approaches for improving our knowledge on melanoma heritability are currently based on segregation analysis coupled with functional assessment of candidate genes. An improvement of computational methods to infer genotype-phenotype correlations could help address the issue of missing heritability.
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http://dx.doi.org/10.1080/14737159.2020.1738221DOI Listing
May 2020

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

J Transl Med 2020 02 13;18(1):78. Epub 2020 Feb 13.

IRCCS Ospedale Policlinico San Martino, Genetics of Rare Cancers, Genoa, Italy.

Background: The 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.

Methods: we 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.

Results: After 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.

Conclusions: MITF+ 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.
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http://dx.doi.org/10.1186/s12967-020-02253-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017513PMC
February 2020

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

PLoS Genet 2019 11 15;15(11):e1008490. Epub 2019 Nov 15.

Biostatistics Branch: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America.

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.
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http://dx.doi.org/10.1371/journal.pgen.1008490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881075PMC
November 2019

Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene.

Carcinogenesis 2020 05;41(3):284-295

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.
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http://dx.doi.org/10.1093/carcin/bgz153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346310PMC
May 2020

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

Lancet Child Adolesc Health 2019 05 12;3(5):332-342. Epub 2019 Mar 12.

Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.

Methods: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger.

Findings: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants.

Interpretation: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.

Funding: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.
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http://dx.doi.org/10.1016/S2352-4642(19)30005-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942319PMC
May 2019

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

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

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.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

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.

Genome Med 2018 12 24;10(1):99. Epub 2018 Dec 24.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.

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.
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http://dx.doi.org/10.1186/s13073-018-0607-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305568PMC
December 2018

Comprehensive Study of the Clinical Phenotype of Germline BAP1 Variant-Carrying Families Worldwide.

J Natl Cancer Inst 2018 12;110(12):1328-1341

Medical Oncology Unit, Ospedale Policlinico San Martino, Genoa, Italy.

Background: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a hereditary tumor syndrome caused by germline pathogenic variants in BAP1 encoding a tumor suppressor associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and cutaneous BAP1-inactivated melanocytic tumors. However, the full spectrum of tumors associated with the syndrome is yet to be determined. Improved understanding of the BAP1-TPDS is crucial for appropriate clinical management of BAP1 germline variant carriers and their families, including genetic counseling and surveillance for new tumors.

Methods: We collated germline variant status, tumor diagnoses, and information on BAP1 immunohistochemistry or loss of somatic heterozygosity on 106 published and 75 unpublished BAP1 germline variant-positive families worldwide to better characterize the genotypes and phenotypes associated with the BAP1-TPDS. Tumor spectrum and ages of onset were compared between missense and null variants. All statistical tests were two-sided.

Results: The 181 families carried 140 unique BAP1 germline variants. The collated data confirmed the core tumor spectrum associated with the BAP1-TPDS and showed that some families carrying missense variants can exhibit this phenotype. A variety of noncore BAP1-TPDS -associated tumors were found in families of variant carriers. Median ages of onset of core tumor types were lower in null than missense variant carriers for all tumors combined (P < .001), mesothelioma (P < .001), cutaneous melanoma (P < .001), and nonmelanoma skin cancer (P < .001).

Conclusions: This analysis substantially increases the number of pathogenic BAP1 germline variants and refines the phenotype. It highlights the need for a curated registry of germline variant carriers for proper assessment of the clinical phenotype of the BAP1-TPDS and pathogenicity of new variants, thus guiding management of patients and informing areas requiring further research.
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http://dx.doi.org/10.1093/jnci/djy171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292796PMC
December 2018

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline mutations.

J Med Genet 2020 05 5;57(5):316-321. Epub 2018 Oct 5.

Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Inherited mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in mutation carriers with metastatic melanoma were evaluated.

Methods: mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic mutation were analysed for association with tumour mutational load.

Results: Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without mutation (Wilcoxon test, p<0.001).

Conclusion: Patients with mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.
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http://dx.doi.org/10.1136/jmedgenet-2018-105610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231460PMC
May 2020

CDKN2A germline mutations are not associated with poor survival in an Italian cohort of melanoma patients.

J Am Acad Dermatol 2019 May 28;80(5):1263-1271. Epub 2018 Sep 28.

Department of Internal Medicine and Medical Specialties, University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background: Cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutations have recently been associated with poor survival in patients with melanoma. Despite the high mutation rate in our cohort (up to 10% in patients with apparently sporadic melanoma), information on the impact of CDKN2A on survival in this cohort is lacking.

Objective: To investigate whether poor survival associated with CDKN2A germline mutations was confirmed in a high mutation-prevalence cohort of Italian patients with melanoma undergoing a mutation-based follow-up.

Methods: A total of 1239 patients with cutaneous melanoma were tested for CDKN2A mutational status and then assigned to a follow-up scheme according not only to family history but also to CDKN2A mutational status, as follow-up intervals were more frequent for CDKN2A germline mutation-positive (MUT) patients. From this cohort, we selected 106 MUT patients (with familial melanoma or apparently sporadic melanoma) and 199 CDKN2A germline mutation-negative (MUT) patients with sporadic melanoma who were matched by age and sex and had a similar tumor stage distribution.

Results: We found no difference in overall survival (hazard ratio, 0.85; 95% confidence interval, 0.48-1.52; P = .592,) or melanoma-specific survival (hazard ratio, 0.86; 95% confidence interval, 0.38-1.95; P = .718,) between MUT and MUT patients. MUT patients were more likely to develop multiple melanomas and to undergo surgical excision of dysplastic nevi than were MUT patients.

Limitations: Retrospective study.

Conclusion: CDKN2A mutations were not associated with survival in our cohort.
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http://dx.doi.org/10.1016/j.jaad.2018.07.060DOI Listing
May 2019

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

J Eur Acad Dermatol Venereol 2018 Dec 14;32(12):2134-2141. Epub 2018 Sep 14.

Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1111/jdv.15208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100361PMC
December 2018

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

Hum Mol Genet 2018 12;27(23):4145-4156

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

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.
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http://dx.doi.org/10.1093/hmg/ddy282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240742PMC
December 2018

Correction: Combining molecular and immunohistochemical analyses of key drivers in primary melanomas: interplay between germline and somatic variations.

Oncotarget 2018 06 19;9(47):28798. Epub 2018 Jun 19.

Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa and Ospedale Policlinico San Martino, Genoa, Italy.

[This corrects the article DOI: 10.18632/oncotarget.23204.].
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http://dx.doi.org/10.18632/oncotarget.25684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033371PMC
June 2018

variants as melanoma risk factors independent of at-risk phenotypic characteristics: a pooled analysis from the M-SKIP project.

Cancer Manag Res 2018 14;10:1143-1154. Epub 2018 May 14.

Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.

Purpose: Melanoma represents an important public health problem, due to its high case-fatality rate. Identification of individuals at high risk would be of major interest to improve early diagnosis and ultimately survival. The aim of this study was to evaluate whether variants predicted melanoma risk independently of at-risk phenotypic characteristics.

Materials And Methods: Data were collected within an international collaboration - the M-SKIP project. The present pooled analysis included data on 3,830 single, primary, sporadic, cutaneous melanoma cases and 2,619 controls from seven previously published case-control studies. All the studies had information on gene variants by sequencing analysis and on hair color, skin phototype, and freckles, ie, the phenotypic characteristics used to define the red hair phenotype.

Results: The presence of any variant was associated with melanoma risk independently of phenotypic characteristics (OR 1.60; 95% CI 1.36-1.88). Inclusion of variants in a risk prediction model increased melanoma predictive accuracy (area under the receiver-operating characteristic curve) by 0.7% over a base clinical model (=0.002), and 24% of participants were better assessed (net reclassification index 95% CI 20%-30%). Subgroup analysis suggested a possibly stronger role of in melanoma prediction for participants without the red hair phenotype (net reclassification index: 28%) compared to paler skinned participants (15%).

Conclusion: The authors suggest that measuring the genotype might result in a benefit for melanoma prediction. The results could be a valid starting point to guide the development of scientific protocols assessing melanoma risk prediction tools incorporating the genotype.
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http://dx.doi.org/10.2147/CMAR.S155283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958947PMC
May 2018
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