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New Insights into Melanoma Tumor Syndromes

  • Sarem Rashid
    Affiliations
    Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Boston University School of Medicine, Boston, Massachusetts, USA
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  • Sameer Gupta
    Affiliations
    Department of Dermatology, The Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA
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  • Shelley R. McCormick
    Affiliations
    Mass General Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA
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  • Hensin Tsao
    Correspondence
    Correspondence: Hensin Tsao, Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
    Affiliations
    Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Open AccessPublished:September 01, 2022DOI:https://doi.org/10.1016/j.xjidi.2022.100152
      Melanoma tumor syndromes (MTS) represent an important minority of familial melanoma cases. In these patients, the accumulation of sequence alterations in essential genes may prelude the risk of internal malignancies, in addition to melanoma. Although several host and environmental factors have been implicated in familial melanoma, the exact mechanisms of cancer predisposition—particularly in the context of mixed cancer syndromes—still remain unclear. In this paper, we review new insights into MTS and elucidate recent efforts that guide individualized prognostication and treatment for these diseases in the past quarter century.

      Abbreviations:

      CI (confidence interval), CS (Cowden syndrome), E2F (E2 factor), FAMMM (familial atypical (multiple) mole melanoma), LFS (Li‒Fraumeni syndrome), LOF (loss-of-function), MTS (melanoma tumor syndrome), NGS (next-generation sequencing), PC (pancreatic cancer), PHTS (PTEN hamartoma tumor syndrome), ssDNA (single-strand DNA), TERT (telomerase reverse transcriptase), TPDS (tumor predisposition syndrome), UM (uveal melanoma)

      Introduction

      Melanoma, the most lethal form of skin cancer, is driven by the complex interplay between genotype and environment. Because UVR exposure remains to be the most significant adverse risk factor for melanoma (
      • Jhappan C.
      • Noonan F.P.
      • Merlino G.
      Ultraviolet radiation and cutaneous malignant melanoma.
      ), one can argue that most melanomas are environmentally induced by excessive sun exposure, with subsequent somatic mutagenesis of melanocytes. However, the risk of exposure is profoundly shaped by inherited factors, such as skin color and the tanning response, which are both genetically determined. Heritable risk for melanoma has been estimated as 58% on the basis of a large twin study comparing melanoma rates in identical (monozygotic) twins with those in nonidentical (dizygotic) twins (
      • Mucci L.A.
      • Hjelmborg J.B.
      • Harris J.R.
      • Czene K.
      • Havelick D.J.
      • Scheike T.
      • et al.
      Familial risk and heritability of cancer among twins in Nordic countries.
      ). Despite this large risk attribution to inheritance, only a fraction has been characterized.
      The earliest attempts to explore these questions were focused on clusters of melanoma cases in families. Approximately 10% of cutaneous melanoma cases occur in patients with a family history of melanoma (
      • Gandini S.
      • Sera F.
      • Cattaruzza M.S.
      • Pasquini P.
      • Zanetti R.
      • Masini C.
      • et al.
      Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors.
      ;
      • Rossi M.
      • Pellegrini C.
      • Cardelli L.
      • Ciciarelli V.
      • Di Nardo L.
      • Fargnoli M.C.
      Familial melanoma: diagnostic and management implications.
      ). Although a cluster of melanoma cases in one family may be, in part, related to shared exposure to environmental risk (same UV exposure), heritable predisposition is assumed to drive pathogenesis (
      • Goldstein A.M.
      • Tucker M.A.
      Genetic epidemiology of cutaneous melanoma: a global perspective.
      ). Heritability was first investigated using linkage analysis, which leverages recombination for positional information in identifying specific loci that are statistically enriched in families with melanoma. Sanger sequencing was used to identify pathogenic variants in CDKN2A and CDK4, which represent 40% of all the heritability in familial cases. For 20 years, these two genes were the only known melanoma susceptibility genes. With the advent of high-throughput sequencing, additional germline variants have been identified and implicated in hereditary melanoma. Population-based studies show a very low frequency of these sequence variants but high disease penetrance (
      • Tsao H.
      • Zhang X.
      • Kwitkiwski K.
      • Finkelstein D.M.
      • Sober A.J.
      • Haluska F.G.
      Low prevalence of germline CDKN2A and CDK4 mutations in patients with early-onset melanoma.
      ;
      • Whiteman D.C.
      • Milligan A.
      • Welch J.
      • Green A.C.
      • Hayward N.K.
      Germline CDKN2A mutations in childhood melanoma.
      ). These low-frequency, high-risk sequence alterations are in contrast to moderate-risk, common, and rare polymorphisms. Large GWASs have identified 54 susceptibility loci for sporadic melanoma (
      • Landi M.T.
      • Bishop D.T.
      • MacGregor S.
      • Machiela M.J.
      • Stratigos A.J.
      • Ghiorzo P.
      • et al.
      Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.
      ), but on their own, these individual loci constitute variants that contribute only small or moderate risks for melanoma.
      In this review, we will focus on melanoma tumor syndromes (MTSs)—those melanomas that arise in the setting of multiple cancer types either within a single individual or within larger kindreds. Tumor syndromes have frequently been linked to high-risk germline variants that collectively define hereditary cancer (Figure 1). MTSs refer to hereditary complexes leading to melanoma at a young age; multiple melanomas in the same individual or family; and an increased risk for other organ malignancies such as pancreatic cancer (PC), renal cell carcinoma, and CNS tumors. Although defining a syndrome on the basis of a polygenic score of low-to-moderate risk loci may be possible in the future, our understanding remains too limiting for such scores to be clinically useful given the heterogenous nature of phenotype risk. Because germline genotypes have become better annotated to cancer phenotypes, the notion of syndromes is quickly being displaced by specific molecular causation rather than clinical findings. We will review the gene syndromes best characterized to date and then explore future perspectives in our understanding of melanoma heritability.
      Figure thumbnail gr1
      Figure 1Integrated molecular pathways in melanoma tumor syndromes. (a) CDKN2A consists of two splice products in alternate reading frames. p16, encoded by exons 1α, 2, and 3, inhibits CDK4, thereby permitting its binding CYCD. This complex subsequently phosphorylates the RB protein which releases E2F and ultimately facilitates G1‒S cell cycle progression. ARF is encoded by exons 1β, 2, and 3 and inhibits HDM2-mediated ubiquitination of p53 (
      • Eskandarpour M.
      • Hashemi J.
      • Kanter L.
      • Ringborg U.
      • Platz A.
      • Hansson J.
      Frequency of UV-inducible NRAS mutations in melanomas of patients with germline CDKN2A mutations.
      ,
      • Foulkes W.D.
      • Flanders T.Y.
      • Pollock P.M.
      • Hayward N.K.
      The CDKN2A (P16) gene and human cancer.
      ,
      • Ruas M.
      • Peters G.
      The P16INK4a/CDKN2A tumor suppressor and its relatives.
      ). (b) As the catalytic subunit of the PR-DUB complex, BAP1 deubiquitinates the H2A complex to regulate cell proliferation, differentiation, metabolism, and apoptosis (
      • Pilarski R.
      • Carlo M.
      • Cebulla C.
      • Abdel-Rahman M.
      BAP1 tumor predisposition syndrome.
      ,
      • Rai K.
      • Pilarski R.
      • Cebulla C.M.
      • Abdel-Rahman M.H.
      Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases.
      ). (c) PTEN functions to negatively regulate PI3K signaling through dephosphorylation of PIP3 to PIP2. Receptor Y kinase‒ and Ras-mediated activation of protein kinases PDK1 and Akt in turn regulates many important proliferative functions (
      • Roh M.R.
      • Gupta S.
      • Park K.H.
      • Chung K.Y.
      • Lauss M.
      • Flaherty K.T.
      • et al.
      Promoter methylation of PTEN is a significant prognostic factor in melanoma survival.
      ,
      • Wu H.
      • Goel V.
      • Haluska F.G.
      PTEN signaling pathways in melanoma.
      ,
      • Zhou X.P.
      • Waite K.A.
      • Pilarski R.
      • Hampel H.
      • Fernandez M.J.
      • Bos C.
      • et al.
      Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway.
      ). (d) TERT and the shelterin complex serve important roles in the regulation of telomere length and chromosomal protection. Recruitment of GABP transcription factor to a mutant TERT promoter region may promote a variety of cancers. Akt, protein kinase B; CYCD, cyclin D; E2F, E2 factor; PI3K, phosphatidylinositide 3-kinase; PIP2, phosphatidylinositol 4,5 bi-phosphate; PIP3, phosphatidylinositol 3,4,5 tri-phosphate; PR-DUB, polycomb repressive deubiquitinase; RB, retinoblastoma; TERT, telomerase reverse transcriptase (
      • Fan Y.
      • Lee Seungjae
      • Wu G.
      • Easton J.
      • Yergeau D.
      • Dummer R.
      • et al.
      Telomerase expression by aberrant methylation of the tert promoter in melanoma arising in giant congenital nevi.
      ,
      • Hafezi F.
      • Perez Bercoff D.
      The solo play of tert promoter mutations.
      ).

      Update On Melanoma Risk Loci

      Retinoblastoma pathway genes

      CDKN2A/CDK4

      Dysplastic nevus syndrome or familial atypical (multiple) mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome resulting from germline variants of several genes, including CDKN2A. Patients will clinically present with numerous atypical nevi (>50, as determined by the ABCDE [asymmetry, border, colors, diameter, evolution] criteria), concerning histologic features (e.g., lymphocytic infiltration, lentiginous melanocytic hyperplasia, and architectural disorder with asymmetry), and a positive family history of melanoma in first- or second-degree relatives (
      • Eckerle M.D.
      • Bishop M.
      • Resse E.
      • Sluzevich J.
      Familial atypical multiple mole melanoma syndrome. Cancer syndromes.
      ) (Figure 2). Although these criteria have been established for clinical diagnosis of FAMMM, it does not describe lesions exclusive to the disorder.
      Figure thumbnail gr2
      Figure 2Clinical Presentation of FAMMM syndrome. FAMMM is an inherited genodermatosis that may clinically present with a high nevus count (often >50 nevi), the presence of atypical appearing nevi, a family history of melanoma, and an increased risk of pancreatic cancer. Careful and routine examination of all body nevi should be performed for high-risk patients, including first- and second-degree relatives. Image published with patient consent. FAMMM, familial atypical multiple mole melanoma.
      CDKN2A and CDK4 are high-penetrance genes associated with an increased risk of familial melanoma. Early genetic linkage analysis proposed at least two high-risk susceptibility loci for melanoma on chromosomal bands 9p21 (
      • Cannon-Albright L.A.
      • Goldgar D.E.
      • Meyer L.J.
      • Lewis C.M.
      • Anderson D.E.
      • Fountain J.W.
      • et al.
      Assignment of a locus for familial melanoma, MLM, to Chromosome 9p13-P22.
      ) and 1p22 (
      • Bale S.J.
      • Dracopoli N.C.
      • Tucker M.A.
      • Clark W.H.
      • Fraser M.C.
      • Stanger B.Z.
      • et al.
      Mapping the Gene for Hereditary cutaneous Malignant Melanoma-Dysplastic Nevus to chromosome 1p.
      ). Shortly after, CDKN2A located in the 9p21 locus was established as a key regulator of cell cycle proteins (CDK4, D-type cyclins, and Rb) (
      • Serrano M.
      • Hannon G.J.
      • Beach D.
      A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
      ). Homozygous deletions found in numerous malignant cell lines were finally established as an important factor for cancer susceptibility (
      • Nobori T.
      • Miura K.
      • Wu D.J.
      • Lois A.
      • Takabayashi K.
      • Carson D.A.
      Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.
      ). CDKN2A encodes isoforms 1 and 4
      The CDKN2A gene encodes for two widely studied proteins p16/INK4A and p14/ARF. The protein p16 inhibits cyclin-dependent protein kinases CDK4 and CDK6, which form a protein complex with cyclin D that functions to phosphorylate the Rb tumor suppressor gene product (
      • Ruas M.
      • Peters G.
      The P16INK4a/CDKN2A tumor suppressor and its relatives.
      ). Phosphorylation of the Rb/E2 factor (E2F) complex by CDK4/6 consequently causes the release of E2F transcription factors that enter the nucleus. These E2F transcription factors are critical regulators of S-phase entry, DNA replication, and cell proliferation (
      • Wu L.
      • Timmers C.
      • Maiti B.
      • Saavedra H.I.
      • Sang L.
      • Chong G.T.
      • et al.
      The E2F1-3 transcription factors are essential for cellular proliferation.
      ). Deregulation of E2F-dependent transcription is thus a hallmark of many human cancers (
      • Johnson D.G.
      • Schneider-Broussard R.
      Role of E2F in cell cycle control and cancer.
      ). In addition to germline CDKN2A inactivation, dysfunction of the Rb pathway may also result from UVR, which is estimated to cause 60‒70% of cutaneous malignant melanomas (
      • Sample A.
      • He Y.Y.
      Mechanisms and prevention of UV-induced melanoma.
      ). The second principle CDKN2A product, p14/ARF, functions through the inhibition of proto-oncogene MDM2 to prevent degradation and ubiquitination of p53 in proliferating cells (
      • Weber H.O.
      • Samuel T.
      • Rauch P.
      • Funk J.O.
      Human P14(ARF)-mediated cell cycle arrest strictly depends on intact P53 signaling pathways.
      ). The majority of germline variants in CDKN2A tend to occur in p16/INK4A rather than in p14/ARF, with a specific preference for exons 1α and 2 (
      • Tsao H.
      • Chin L.
      • Garraway L.A.
      • Fisher D.E.
      Melanoma: from mutations to medicine.
      ).
      Germline CDKN2A sequence variants most frequently occur in exons 1‒3 (
      • Foulkes W.D.
      • Flanders T.Y.
      • Pollock P.M.
      • Hayward N.K.
      The CDKN2A (P16) gene and human cancer.
      ). In exon 2, c.225-243del and c.301G>T are among the most frequent variants in FAMMM kindreds (
      • Foulkes W.D.
      • Flanders T.Y.
      • Pollock P.M.
      • Hayward N.K.
      The CDKN2A (P16) gene and human cancer.
      ).
      • Hussussian C.J.
      • Struewing J.P.
      • Goldstein A.M.
      • Higgins P.A.
      • Ally D.S.
      • Sheahan M.D.
      • et al.
      Germline P16 mutations in familial melanoma.
      described eight p16 germline variants—one splice donor-site, one nonsense, and six missense variants—occurring in 13 of 18 familial melanoma kindreds. Of these variants, six were reported in 33 of 36 melanoma cases in nine families. Another Dutch study reported a germline deletion (19 basepair length) in 13 of 15 families with FAMMM (
      • Gruis N.A.
      • van der Velden P.A.
      • Sandkuijl L.A.
      • Prins D.E.
      • Weaver-Feldhaus J.
      • Kamb A.
      • et al.
      Homozygotes for CDKN2 (P16) germline mutation in Dutch familial melanoma kindreds.
      ). This deletion produces a shift in reading frame, thereby truncating the p16 protein. Strikingly, heterozygous patients in this group exhibited a more severe phenotype than homozygous family members, suggesting a clinically relevant compensatory mechanism in p16 deficiency, which requires further exploration (
      • McWilliams R.R.
      • Wieben E.D.
      • Rabe K.G.
      • Pedersen K.S.
      • Wu Y.
      • Sicotte H.
      • et al.
      Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling.
      ). Finally, an Italian study showed three cases of PC detected in seven melanoma-prone families containing a Gly101Trp missense variant (
      • Ciotti P.
      • Strigini P.
      • Bianchi-Scarrà G.
      Familial melanoma and pancreatic cancer. Ligurian skin tumor study group.
      ).
      The association between germline CDKN2A variants and PC is well-established. In a previous study, 28% of melanoma-prone families harboring a germline CDKN2A variants were found to have PC (compared with 6% of families harboring no CDKN2A variant) (
      • Goldstein A.M.
      • Chan M.
      • Harland M.
      • Gillanders E.M.
      • Hayward N.K.
      • Avril M.-F.
      • et al.
      High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.
      ). From this sample, 45% of CDKN2A-mutant families with neural system tumors reported at least one case of PC, although these studies utilize small patient samples. The frequency of PC was found to be greatest (>60%) in patients with p.R112_L113insR and c.225_24del19 CDKN2A variants and to be least (<11%) in patients with p.M53I, c.IVS2-105A>G, and c.32_33ins9-32 variants (
      • Eckerle M.D.
      • Bishop M.
      • Resse E.
      • Sluzevich J.
      Familial atypical multiple mole melanoma syndrome. Cancer syndromes.
      ). Results from the GenoMEL study show that CDK2NA variants in kindreds with melanoma with PC are more likely to affect both p16 and p14ARF (49%) than p16 alone (26%) (
      • Goldstein A.M.
      • Chan M.
      • Harland M.
      • Gillanders E.M.
      • Hayward N.K.
      • Avril M.-F.
      • et al.
      High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.
      ;
      • McWilliams R.R.
      • Wieben E.D.
      • Rabe K.G.
      • Pedersen K.S.
      • Wu Y.
      • Sicotte H.
      • et al.
      Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling.
      ). Outside of the melanoma phenotype, between 1.5% and 3.3% of patients with familial PC harbor germline CDKN2A variants (
      • Kimura H.
      • Klein A.P.
      • Hruban R.H.
      • Roberts N.J.
      The role of inherited pathogenic CDKN2A variants in susceptibility to pancreatic cancer.
      ).
      Inactivating CDKN2A germline variants may also confer an increased risk of astrocytoma in addition to melanoma, for example, in familial melanoma‒astrocytoma syndrome (
      • Chan A.K.
      • Han S.J.
      • Choy W.
      • Beleford D.
      • Aghi M.K.
      • Berger M.S.
      • et al.
      Familial melanoma-astrocytoma syndrome: synchronous diffuse astrocytoma and pleomorphic xanthoastrocytoma in a patient with germline CDKN2A/B deletion and a significant family history.
      ). In a 1993 case report,
      • Kaufman D.K.
      • Kimmel D.W.
      • Parisi J.E.
      • Michels V.V.
      A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma.
      first described a family affected by cutaneous melanoma and cerebral astrocytoma over three successive generations. Through linkage analysis, this disorder was later characterized by deletions of chromosome 9p21.3 at the INK4 locus, which encodes for tumor suppressor genes CDKN2A and CDKN2B (
      • Bahuau M.
      • Vidaud D.
      • Jenkins R.B.
      • Bièche I.
      • Kimmel D.W.
      • Assouline B.
      • et al.
      Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.
      , 4). The full spectrum and histology of nervous-system tumors in familial melanoma‒astrocytoma syndrome is not currently well-described.
      CDK4, the cognate target of p16, is also mutationally activated in a small number of FAMMM kindreds. All sequence variants of CDK4 have been described to occur in exon 2, which is the site of the p16:CDK4 interaction; mutagenesis of this site abrogates p16 binding (
      • Rossi M.
      • Pellegrini C.
      • Cardelli L.
      • Ciciarelli V.
      • Di Nardo L.
      • Fargnoli M.C.
      Familial melanoma: diagnostic and management implications.
      ;
      • Zuo L.
      • Weger J.
      • Yang Qingbei
      • Goldstein A.M.
      • Tucker M.A.
      • Walker G.J.
      • et al.
      Germline mutations in the P16INK4a binding domain of CDK4 in familial melanoma.
      ). Patients with germline CDK4 variants cannot be differentiated phenotypically from those with germline CDKN2A variants (
      • Puntervoll H.E.
      • Yang X.R.
      • Vetti H.H.
      • Bachmann I.M.
      • Avril M.F.
      • Benfodda M.
      • et al.
      Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants.
      ).
      Although a single consensus that covers the clinical management of patients with FAMMM has yet to be determined, regular total body skin examinations are essential. Depending on the number of atypical nevi, individuals with FAMMM should be examined at least every 6‒12 months, and self-surveillance measures should be emphasized by the dermatologist. For PC, the National Comprehensive Cancer Network screening guidelines (www.nccn.org, version 2.2022) recommend that individuals with a known pathogenic germline variant in a PC susceptibility gene (e.g., CDKN2A) and a family history of PC undergo surveillance with magnetic resonance imaging and/or endoscopic ultrasound. Whether CDKN2A variant carriers from hereditary melanoma kindreds, in the absence of any PC affected, require the same rigorous PC screening has not been fully established.

      RB1

      Multiple publications have reported an increased risk of melanoma among patients with retinoblastoma who carry germline variants in the RB1 gene. In a survey of 1,927 patients with retinoblastoma (
      • MacCarthy A.
      • Bayne A.M.
      • Brownbill P.A.
      • Bunch K.J.
      • Diggens N.L.
      • Draper G.J.
      • et al.
      Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951–2004.
      ) diagnosed in Britain between 1951 and 2004, there were 12 cases of melanoma among patients with heritable retinoblastoma, yielding a standardized incidence ratio of 18.6 (9.6‒32.4). Thus, a consensus panel convened in 2020 strongly recommended an annual skin examination for survivors of retinoblastoma with a single-skin examination before age 8 years and annual skin examinations with adequate sun protection measures after adolescence (
      • Tonorezos E.S.
      • Friedman D.N.
      • Barnea D.
      • Bosscha M.I.
      • Chantada G.
      • Dommering C.J.
      • et al.
      Pim de Graaf, et al Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma.
      ).

      BAP1

      In 1998,
      • Jensen D.E.
      • Proctor M.
      • Marquis S.T.
      • Gardner H.P.
      • Ha S.I.
      • Chodosh L.A.
      • et al.
      BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 ring finger and enhances BRCA1-mediated cell growth suppression.
      discovered a novel ubiquitin carboxy-terminal hydrolase that attached to the wild-type BRCA1-RING finger in certain breast cancers. Since then, BAP1 has been established as a tumor suppressor gene involved in transcription modulation (YY1, FOXK1, FOXK2), response to extracellular stress and DNA-damage repair (MBD5, MBD6), and chromatin modification (ASXL1, ASXL3, KDM1B, OGT1) through independent mechanisms (
      • Baymaz H.I.
      • Fournier A.
      • Laget S.
      • Ji Z.
      • Jansen P.W.
      • Smits A.H.
      • Ferry L.
      • et al.
      MBD5 and MBD6 interact with the human PR-DUB complex through their methyl-CpG-binding domain.
      ;
      • Campagne A.
      • Lee M.-K.
      • Zielinski D.
      • Michaud A.
      • Le Corre S.
      • Dingli F.
      • et al.
      BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation.
      ;
      • Ji Z.
      • Mohammed H.
      • Webber A.
      • Ridsdale J.
      • Han Namshik
      • Carroll J.S.
      • et al.
      The forkhead transcription factor FOXK2 acts as a chromatin targeting factor for the BAP1-containing histone deubiquitinase complex.
      ;
      • Yu H.
      • Mashtalir N.
      • Daou S.
      • Hammond-Martel I.
      • Ross J.
      • Sui G.
      • et al.
      The ubiquitin carboxyl hydrolase BAP1 forms a ternary complex with YY1 and HCF-1 and is a critical regulator of gene expression.
      ). Subsequent experiments by
      • Ventii K.H.
      • Devi N.S.
      • Friedrich K.L.
      • Chernova T.A.
      • Tighiouart M.
      • Van Meir E.G.
      • et al.
      BRCA1-associated Protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
      suggested tumor growth suppression of BAP1-restored lung cancers in animal models. Suppression of tumorgenicity may be due to cell cycle disruption, at the G1/S checkpoint for example, or induction of apoptosis (
      • Ventii K.H.
      • Devi N.S.
      • Friedrich K.L.
      • Chernova T.A.
      • Tighiouart M.
      • Van Meir E.G.
      • et al.
      BRCA1-associated Protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
      ). Germline sequence variants in BAP1 have been linked to increased risks for renal cell carcinoma, mesothelioma, and melanoma (uveal and cutaneous) (
      • Louie B.H.
      • Kurzrock R.
      BAP1: not just a BRCA1-associated protein.
      ). The exact nature of BAP1’s molecular function remains unclear given the diverse role of ubiquitination in physiologic maintenance.
      A connection between BAP1 and melanoma was first established through somatic analyses of uveal melanoma (UM) specimens.
      • Harbour J.W.
      • Onken M.D.
      • Roberson E.D.
      • Duan S.
      • Cao L.
      • Worley L.A.
      • et al.
      Frequent mutation of BAP1 in metastasizing uveal melanomas.
      found inactivating BAP1 variants in 84% of metastatic UM cases. Shortly thereafter, germline variants of BAP1 were detected in kindreds with mixed tumors, including peritoneal and pulmonary mesotheliomas, meningiomas, UM and cutaneous melanoma, and renal cell carcinomas (
      • Abdel-Rahman M.H.
      • Pilarski R.
      • Cebulla C.M.
      • Massengill J.B.
      • Christopher B.N.
      • Boru G.
      • et al.
      Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.
      ;
      • Carbone M.
      • Yang H.
      • Pass H.I.
      • Krausz T.
      • Testa J.R.
      • Gaudino G.
      BAP1 and cancer.
      ;
      • Testa J.R.
      • Cheung M.
      • Pei J.
      • Below J.E.
      • Tan Yinfei
      • Sementino E.
      • et al.
      Germline BAP1 mutations predispose to malignant mesothelioma.
      ).
      Germline variants in the BAP1 gene are inherited in an autosomal dominant pattern (
      • Masoomian B.
      • Shields J.A.
      • Shields C.L.
      Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma.
      ). The incidence of de novo sequence alterations in BAP1 tumor predisposition syndrome (TPDS) has yet to be established (
      • Pilarski R.
      • Carlo M.
      • Cebulla C.
      • Abdel-Rahman M.
      BAP1 tumor predisposition syndrome.
      ). The gene exhibits incomplete penetrance, and incidence and tumor type may vary among members of the same family (
      • Carbone M.
      • Yang H.
      • Pass H.I.
      • Krausz T.
      • Testa J.R.
      • Gaudino G.
      BAP1 and cancer.
      ).
      From the skin perspective, inactivation of this gene may predispose an individual to BAP1-inactivated melanocytic tumors, formerly called atypical Spitz tumors, and a subsequent diagnosis of BAP1 TPDS (
      • Masoomian B.
      • Shields J.A.
      • Shields C.L.
      Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma.
      ). BAP1-inactivated melanocytic tumors clinically appear as dome-shaped papules or nodules located on the face or extremities (
      • Masoomian B.
      • Shields J.A.
      • Shields C.L.
      Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma.
      ). These tumors may show absent mitotic figures and the presence of Kamino bodies (
      • Wiesner T.
      • Obenauf A.C.
      • Murali R.
      • Fried I.
      • Griewank K.G.
      • Ulz P.
      • et al.
      Germline mutations in BAP1 predispose to melanocytic tumors.
      ). Because the lesion carries a diverse histopathological spectrum that closely resembles that of melanoma, high interobserver variability has been reported among dermatologists (
      • Filiberto A.
      • Fuller C.
      • Rhodes J.
      Atypical Spitz nevi: a case report and review of the literature.
      ). However, UM is the most common cancer found in BAP1 TPDS (36.2% occurrence in probands compared with 23.4 and 15.0% occurrence in probands for cutaneous melanoma and nonmelanoma skin cancers, respectively) (
      • Walpole S.
      • Pritchard A.L.
      • Cebulla C.M.
      • Pilarski R.
      • Stautberg M.
      • Davidorf F.H.
      • et al.
      Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide.
      ). Tumors with this allelic variant may be more aggressive, with a high propensity to metastasize (
      • Rai K.
      • Pilarski R.
      • Cebulla C.M.
      • Abdel-Rahman M.H.
      Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases.
      ). Altogether, germline BAP1 variants can be designated by a phenotypic complex containing cutaneous and ocular melanomas, characteristic melanocytic proliferations, and other internal neoplasms; for this reason, BAP1 TPDS is sometimes referred to as COMMON syndrome (
      • Njauw C.-N.J.
      • Kim I.
      • Piris A.
      • Gabree M.
      • Taylor M.
      • Lane A.M.
      • et al.
      Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families.
      ). These tumors, although present in other germline susceptibilities, have reportedly worse outcomes (
      • Gupta M.P.
      • Lane A.M.
      • DeAngelis M.M.
      • Mayne K.
      • Crabtree M.
      • Gragoudas E.S.
      • et al.
      Clinical characteristics of uveal melanoma in patients with germline BAP1 mutations.
      ) than tumors without the sequence variant.
      Given the rarity of individuals with germline BAP1 variants, there is currently no consensus for medical management—although annual skin and eye examinations may be plausible in addition to routine imaging surveillance of the abdomen and chest (
      • Pilarski R.
      • Carlo M.
      • Cebulla C.
      • Abdel-Rahman M.
      BAP1 tumor predisposition syndrome.
      ).

      Human telomerase reverse transcriptase promoter sequence alterations and the shelterin complex

      Human telomerase reverse transcriptase promoter

      Telomerase reactivation or re-expression is a common process in tumorigenesis (
      • Vinagre J.
      • Almeida A.
      • Pópulo H.
      • Batista R.
      • Lyra J.
      • Pinto V.
      • et al.
      Frequency of tert promoter mutations in human cancers.
      ). The absence of telomerase in normal tissue causes progressive telomeric decay owing to DNA polymerase activity. As telomeric length decreases, thereby losing its function, the DNA damage response pathway is activated. Replicative senescence is subsequently induced to mitigate uncontrolled proliferation in precancerous cells (
      • Yuan X.
      • Larsson C.
      • Xu D.
      Mechanisms underlying the activation of tert transcription and telomerase activity in human cancer: old actors and new players.
      ). Therefore, telomerase activation is an important mechanism used to bypass physiologic brakes involved in cell growth.
      Germline variants in the telomerase reverse transcriptase (TERT) gene TERT promoter region have been identified (chr5:1295161 T>G, GRCh37/hg19) in a single family with familial melanoma using linkage analysis followed by next-generation sequencing (NGS) (
      • Horn S.
      • Figl A.
      • Rachakonda P.S.
      • Fischer C.
      • Sucker A.
      • Gast A.
      • et al.
      Tert promoter mutations in familial and sporadic melanoma.
      ); a second independent family with the identical promoter variant was also reported in a cohort screen of 675 families with melanoma (
      • Harland M.
      • Petljak M.
      • Robles-Espinoza C.D.
      • Ding Z.
      • Gruis N.A.
      • van Doorn R.
      • et al.
      Germline tert promoter mutations are rare in familial melanoma.
      ). This sequence variant generated a new binding motif for ETS domain proteins, which link transcription to the MAPK signaling pathway. Family members showed early onset melanoma (mean = 34 years) and high susceptibility to other primary tumors affecting the ovaries, kidneys, breast, and lungs. A recent report found TERT promoter CpG dinucleotide methylation to be associated with decreased recurrence-free melanoma survival in adolescents and young adults (
      • Seynnaeve B.
      • Lee Seungjae
      • Borah S.
      • Park Y.
      • Pappo A.
      • Kirkwood J.M.
      • et al.
      Genetic and epigenetic alterations of tert are associated with inferior outcome in adolescent and young adult patients with melanoma.
      ). TERT hypermethylation has been associated with tumor progression and poorer prognosis in previous brain and prostate tumor studies (
      • Castelo-Branco P.
      • Choufani S.
      • Mack S.
      • Gallagher D.
      • Zhang C.
      • Lipman T.
      • et al.
      Methylation of the tert promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study.
      ;
      • Castelo-Branco P.
      • Leão R.
      • Lipman T.
      • Campbell B.
      • Lee D.
      • Price A.
      • et al.
      A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: a retrospective cohort study.
      ). Benign tissue should show minimal methylation of CpG dinucleotides (
      • Lee S.
      • Borah S.
      • Bahrami A.
      Detection of aberrant tert promoter methylation by combined bisulfite restriction enzyme analysis for cancer diagnosis.
      ), which serves as an important factor for diagnostic purposes.
      Somatic germline alterations of the TERT promoter region are relatively common in cutaneous melanomas and are associated with decreased disease-free survival and increased rate of metastasis, particularly when coupled to BRAF and NRAS alterations (
      • Hugdahl E.
      • Kalvenes M.B.
      • Mannelqvist M.
      • Ladstein R.G.
      • Akslen L.A.
      Prognostic impact and concordance of tert promoter mutation and protein expression in matched primary and metastatic cutaneous melanoma.
      ;
      • Nagore E.
      • Heidenreich B.
      • Requena C.
      • García-Casado Z.
      • Martorell-Calatayud A.
      • Pont-Sanjuan V.
      • et al.
      Tert promoter mutations associate with fast-growing melanoma.
      ;
      • Chang G.A.
      • Wiggins J.M.
      • Corless B.C.
      • Syeda M.M.
      • Tadepalli J.S.
      • Blake S.
      • et al.
      TERT, BRAF, and NRAS mutational heterogeneity between paired primary and metastatic melanoma tumors.
      ). The most commonly observed sequence variant, TERTp (C>T transition), has been associated with poor prognosis in multiple studies (
      • Campos M.A.
      • Macedo S.
      • Fernandes M.
      • Pestana A.
      • Pardal J.
      • Batista R.
      • et al.
      Tert promoter mutations are associated with poor prognosis in cutaneous squamous cell carcinoma.
      ;
      • Hafezi F.
      • Perez Bercoff D.
      The solo play of tert promoter mutations.
      ). The hypermethylation status of CpG islands may also serve as a molecular landmark to discriminate advanced melanocytic nevi (
      • Fan Y.
      • Lee Seungjae
      • Wu G.
      • Easton J.
      • Yergeau D.
      • Dummer R.
      • et al.
      Telomerase expression by aberrant methylation of the tert promoter in melanoma arising in giant congenital nevi.
      ). In this study, TERT promoter varaints or hypermethylation were harbored exclusively in melanomas and were notably absent in benign or low-grade melanocytic lesions. More recently,
      • Thomas N.E.
      • Edmiston S.N.
      • Tsai Y.S.
      • Parker J.S.
      • Googe P.B.
      • Busam K.J.
      • et al.
      Utility of tert promoter mutations for cutaneous primary melanoma diagnosis.
      reported TERT promoter variants in 77.9% of confirmed melanomas. In contrast, only 5.0% of diagnostically uncertain melanomas contained such sequence alterations. Future improvements in methylation assays, together with high-throughput sequencing, may allow for increased clinical prognostication for patients with melanoma with TERT alterations.

      POT1

      Telomeres consist of repeated DNA sequences and proteins that comprise the terminal ends of each chromosome. In somatic cells, progressive telomeric elongation is thought to contribute to genomic damage and the immortal phenotype of cancer cells (
      • Henry M.L.
      • Osborne J.
      • Else T.
      POT1 tumor predisposition.
      ). The shelterin complex or telosome binds both single-strand DNA (ssDNA) and double-strand DNA regions of telomeres to downregulate physiologic DNA damage signaling (
      • Lim C.J.
      • Cech T.R.
      Shaping human telomeres: from Shelterin and CST complexes to telomeric chromatin organization [published correction appears in Nat Rev Mol Cell Biol 2021;22:299.
      ). Shelterin is composed of six protein subunits: TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. After binding to DNA, this assembly may yield various DNA-protective conformations such as the end-capped telomere and telomere loop (
      • Lim C.J.
      • Cech T.R.
      Shaping human telomeres: from Shelterin and CST complexes to telomeric chromatin organization [published correction appears in Nat Rev Mol Cell Biol 2021;22:299.
      ).
      The POT1 gene is critical for shelterin complex formation and binding to telomeric ssDNA through its interaction with TPP1 (
      • Henry M.L.
      • Osborne J.
      • Else T.
      POT1 tumor predisposition.
      ). POT1 is located at 7q31.33, and variants have been reported at isoform 1 of the protein (
      • Müller C.
      • Krunic M.
      • Wendt J.
      • von Haeseler A.
      • Okamoto I.
      Germline variants in the POT1-gene in high-risk melanoma patients in Austria.
      ). Germline variants in this gene have been implicated in familial melanoma predisposition in addition to the development of other tumors such as chronic lymphocytic leukemia, angiosarcomas, and gliomas (
      • Calvete O.
      • Garcia-Pavia P.
      • Domínguez F.
      • Bougeard G.
      • Kunze K.
      • Braeuninger A.
      • et al.
      The wide spectrum of POT1 gene variants correlates with multiple cancer types.
      ). In 2014, a POT1 founder sequence alteration (chromosome 7: g.124493086C>T; p.Ser270Asn) was found in five melanoma-prone families from Romagna, Italy (
      • Shi J.
      • Yang X.R.
      • Ballew B.
      • Rotunno M.
      • Calista D.
      • Fargnoli M.C.
      • et al.
      Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma.
      ). In another study, four additional POT1 variants were identified in melanoma families: (i) g.124503684T>C, (ii) g.124465412C>T, (iii) g.124503670G>C, and (iv) g.124493077C>A (
      • Robles-Espinoza C.D.
      • Harland M.
      • Ramsay A.J.
      • Aoude L.G.
      • Quesada V.
      • Ding Z.
      • et al.
      POT1 loss-of-function variants predispose to familial melanoma.
      ). Eight high-risk melanoma POT1 variants were also observed in Austrian patients in a more recent study (
      • Müller C.
      • Krunic M.
      • Wendt J.
      • von Haeseler A.
      • Okamoto I.
      Germline variants in the POT1-gene in high-risk melanoma patients in Austria.
      ). Variants associated with different tumor types are observed to be randomly distributed along the gene (
      • Calvete O.
      • Garcia-Pavia P.
      • Domínguez F.
      • Bougeard G.
      • Kunze K.
      • Braeuninger A.
      • et al.
      The wide spectrum of POT1 gene variants correlates with multiple cancer types.
      ). Owing to the wide spectrum of POT1 variants and associated cancers, further study of this gene is required to elucidate the putative relationship between melanoma and POT1 dysfunction.

      ACD gene

      Adrenocortical dysplasia gene ACD encodes a second shelterin complex protein factor called TPP1, which has been implicated in telomerase recruitment and activity (
      • Henslee G.
      • Williams C.L.
      • Liu P.
      • Bertuch A.A.
      Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.
      ). When bound to POT1, ACD inhibits the elongation of telomeric chromosomal ends and increases the affinity for POT1 to bind ssDNA (
      • Loayza D.
      • De Lange T.
      POT1 as a terminal transducer of TRF1 telomere length control.
      ). Whole-exome sequencing of 113 families with familial melanoma revealed six families with ACD variants (
      • Aoude L.G.
      • Pritchard A.L.
      • Robles-Espinoza C.D.
      • Wadt K.
      • Harland M.
      • Choi J.
      • et al.
      Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
      ). The majority of cases were observed to be superficial spreading or lentigo maligna melanomas. A p.N249S variant was observed in two families, which has also been shown to occur in the POT1-binding domain.

      TER2F1P

      A third gene implicated in the shelterin complex, TERF2IP, acts to regulate telomere length by repressing homology-directed repair (
      • Rai R.
      • Chen Y.
      • Lei M.
      • Chang S.
      TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions.
      ). In the cytoplasm, TERF2IP associates with the Ik-B kinase complex to activate the expression of proinflammatory NF-kB-target genes (
      • Teo H.
      • Ghosh S.
      • Luesch H.
      • Ghosh A.
      • Wong E.T.
      • Malik N.
      • et al.
      Telomere-independent Rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression.
      ).
      • Aoude L.G.
      • Pritchard A.L.
      • Robles-Espinoza C.D.
      • Wadt K.
      • Harland M.
      • Choi J.
      • et al.
      Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
      found TERF2IP variants in 4 of 510 families, with the majority of cases again resembling either superficial spreading or lentigo maligna melanomas.

      MITF

      MITF encodes a bHLH-Zip (basic-helix-loop-helix-leucine zipper) motif and is a key factor in melanocyte regulation (
      • McGill G.G.
      • Horstmann M.
      • Widlund H.R.
      • Du J.
      • Motyckova G.
      • Nishimura E.K.
      • et al.
      Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability.
      ). In 2005,
      • Garraway L.A.
      • Widlund H.R.
      • Rubin M.A.
      • Getz G.
      • Berger A.J.
      • Ramaswamy S.
      • et al.
      Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
      observed that MITF alterations may be predictive of metastatic disease, patient survival, and chemotherapeutic response. Autosomal dominant variants of this gene have been linked to Waardenburg syndrome type IIA, a genetic disorder characterized by deafness and pigmentation abnormalities of the skin, eyes, and hair (
      • Nobukuni Y.
      • Watanabe A.
      • Takeda K.
      • Skarka H.
      • Tachibana M.
      Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A.
      ).
      The MITF(E318K) variant is of particular interest because it carries at least a two-fold increased risk of melanoma (
      • Bertolotto C.
      • Lesueur F.
      • Giuliano S.
      • Strub T.
      • de Lichy M.
      • Bille K.
      • et al.
      A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.
      ;
      • Guhan S.M.
      • Artomov M.
      • McCormick S.
      • Njauw C.
      • Stratigos A.J.
      • Shannon K.
      • et al.
      Cancer risks associated with the germline MITF(E318K) variant.
      ). In normoxia, SUMO proteins bind to MITF, thereby decreasing the transcription of the HIF1A. Sequence alterations at codon 318 downregulate SUMOylation of MITF and consequently increase binding to the HIF1A promoter when compared with that of wild-type MITF. Patients with this variant are observed to have higher median nevus count and melanoma incidence (
      • Ciccarese G.
      • Dalmasso B.
      • Bruno W.
      • Queirolo P.
      • Pastorino L.
      • Andreotti V.
      • et al.
      Clinical, pathological and dermoscopic phenotype of MITF p.E318K carrier cutaneous melanoma patients.
      ). Histologically, a greater proportion of nodular melanomas were observed in tumors containing this variant. A meta-analysis of nine studies conducted on both sporadic and hereditary melanoma families revealed a significant correlation of the MITF(E318K) variant with melanoma risk (OR = 2.37, 95% confidence interval [CI] = 1.89‒2.97) and uterine sarcoma (OR = 9.24, 95% CI = 2.08–37.17) (
      • Guhan S.M.
      • Artomov M.
      • McCormick S.
      • Njauw C.
      • Stratigos A.J.
      • Shannon K.
      • et al.
      Cancer risks associated with the germline MITF(E318K) variant.
      ). There are inconsistent findings to date regarding the association of this variant with PC and renal cell carcinoma.

      ATM gene

      Variants in ataxia–telangiectasia mutated gene ATM have been linked to multiple cancers in GWASs, including melanoma (
      • Landi M.T.
      • Bishop D.T.
      • MacGregor S.
      • Machiela M.J.
      • Stratigos A.J.
      • Ghiorzo P.
      • et al.
      Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.
      ). ATM encodes for a kinase involved in double-stranded break repair in DNA and has been linked to a broad spectrum of cell processes such as cell metabolism, oxidative stress, and genome stability (
      • Cremona C.A.
      • Behrens A.
      ATM signalling and cancer.
      ). The role of ATM as a tumor suppressor gene is summarized by two pathways: (i) a canonical pathway in which ATM complexes with the Mre11-Rad50-NBS1 at double-stranded breaks and (ii2) a non-canonical pathway involving ATMIN (ATM Interactor) or ATR proteins (
      • Cremona C.A.
      • Behrens A.
      ATM signalling and cancer.
      ). Autosomal recessive inactivation of ATM may cause ataxia‒telangiectasia, also known as Louis‒Bar syndrome, which is characterized by ataxia, telangiectasias, immunodeficiencies, and increased cancer predisposition (
      • Riboldi G.M.
      • Samanta D.
      • Frucht S.
      Ataxia telangiectasia.
      ). A recent analysis of the Genome Aggregation Database found that loss-of-function (LOF) variants were more prevalent in melanoma patients (0.95% in the whole cohort) than in a subset of non‒Finnish European control patients (0.36% in the control sample) (
      • Dalmasso B.
      • Pastorino L.
      • Nathan V.
      • Shah N.N.
      • Palmer J.M.
      • Howlie M.
      • et al.
      Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.
      ). A slightly increased prevalence of ATM LOF variants was observed in familial and multiple primary melanoma cases (1.08% in the cohort). Because the majority of these variants were observed in melanoma-prone families, ATM may indeed function as a moderate-risk gene in melanoma similar to that in breast cancer (
      • Cavaciuti E.
      • Laugé A.
      • Janin N.
      • Ossian K.
      • Hall J.
      • Stoppa-Lyonnet D.
      • et al.
      Cancer risk according to type and location of ATM mutation in Ataxia-telangiectasia families.
      ).

      Defined Mixed-Tumor Syndromes With Increased Melanoma Risk

      PTEN

      PTEN is an important tumor suppressor and modifier of the host immune response in many cancers (
      • Chen C.Y.
      • Chen J.C.
      • He L.
      • Stiles B.L.
      PTEN: tumor suppressor and metabolic regulator.
      ;
      • Wu H.
      • Goel V.
      • Haluska F.G.
      PTEN signaling pathways in melanoma.
      ). The tumor suppressor gene encodes a lipid phosphatase that negatively regulates the phosphatidylinositide 3-kinase/protein kinase B (Akt) signaling pathway. The binding of cell surface receptors increases intracellular levels of cytosolic secondary messenger phosphatidylinositol phosphate, eventually resulting in the phosphorylation of the oncogene Akt. PTEN loss or alteration has been reported in sporadic tumors (
      • Bruni P.
      • Boccia A.
      • Baldassarre G.
      • Trapasso F.
      • Santoro M.
      • Chiappetta G.
      • et al.
      PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27Kip1.
      ) as well as in hereditary tumor syndromes (
      • Birck A.
      • Ahrenkiel V.
      • Zeuthen J.
      • Hou-Jensen K.
      • Guldberg P.
      Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies.
      ).
      PTEN loss manifests as a complex spectrum of disorders called PTEN hamartoma tumor syndrome (PHTS) (
      • Innella G.
      • Bonora E.
      • Neri I.
      • Virdi A.
      • Guglielmo A.
      • Pradella L.M.
      • et al.
      PTEN hamartoma tumor syndrome: skin manifestations and insights into their molecular pathogenesis.
      ). Patients with PHTS will primarily exhibit numerous hamartomas and a high risk of multisystem tumor development, although they may suffer from rarer genetic disorders such as Cowden syndrome (CS), Lhermitte‒Duclos disease, Bannayan‒Riley‒Ruvalcaba syndrome, and autism spectrum disorders (
      • Pilarski R.
      PTEN hamartoma tumor syndrome: a clinical overview.
      ) (Table 1). More than 100 germline variations for PTEN have been suspected in patients suffering from CS and Bannayan‒Riley‒Ruvalcaba syndrome (
      • Bonneau D.
      • Longy M.
      Mutations of the human PTEN gene.
      ). Despite large genetic heterogeneity, 10% of patients with CS without coding region variants harbor identifiable promoter variants (
      • Zhou X.P.
      • Waite K.A.
      • Pilarski R.
      • Hampel H.
      • Fernandez M.J.
      • Bos C.
      • et al.
      Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway.
      ). Approximately 20‒30% of germline and somatic PTEN alterations occur on exon 5, which encodes for a phosphatase core domain (
      • Wu H.
      • Goel V.
      • Haluska F.G.
      PTEN signaling pathways in melanoma.
      ).
      Table 1Summary of Melanoma Tumor Syndromes according to Susceptibility Gene
      SubtypeGeneSyndromeInheritance PatternAssociated Nonmelanoma Tumors
      Melanoma-dominant syndromesCDKN2A and CD4Familial atypical multiple mole melanoma syndrome or dysplastic nevus syndromeAutosomal dominantPancreatic cancer, astrocytoma (familial melanoma-astrocytoma syndrome)
      BAP1BAP1 tumor predisposition syndrome or COMMON syndromeAutosomal dominantBAP1-inactivated melanocytic tumors (Spitz tumors), basal cell carcinoma, renal cell carcinoma, mesothelioma
      Melanoma-associated syndromesPTENPTEN hamartoma tumor syndromeAutosomal dominantHamartomas, Cowden syndrome, Lhermitte‒Duclos disease, Bannayan‒Riley‒Ruvalcaba syndrome, facial trichilemmomas, mucocutaneous neuromas, cutaneous lipomas
      TERTBothOvarian cancer, kidney cancer, breast cancer, bladder cancer, lung cancer
      TP53Li‒Fraumeni syndromeAutosomal dominantBreast cancer, soft tissue sarcoma, Osteosarcoma, leukemia, adrenal cortical tumors
      A number of skin lesions have been reported in PHTS. Skin involvement may occur before the age of 40 years as facial trichilemmomas (
      • Brownstein M.H.
      • Mehregan A.H.
      • Bikowski J.B.
      • Lupulescu A.
      • Patterson J.C.
      The dermatopathology of Cowden’s syndrome.
      ), mucocutaneous neuromas (
      • Schaffer J.V.
      • Kamino H.
      • Witkiewicz A.
      • McNiff J.M.
      • Orlow S.J.
      Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome.
      ), benign acral keratoses (
      • Brownstein M.H.
      • Mehregan A.H.
      • Bikowski J.B.
      • Lupulescu A.
      • Patterson J.C.
      The dermatopathology of Cowden’s syndrome.
      ), and cutaneous lipomas (
      • Buisson P.
      • Leclair M.-D.
      • Jacquemont S.
      • Podevin G.
      • Camby C.
      • David A.
      • et al.
      Cutaneous lipoma in children: 5 cases with Bannayan-Riley-Ruvalcaba syndrome.
      ;
      • Haibach H.
      • Burns T.W.
      • Carlson H.E.
      • Burman K.D.
      • Deftos L.J.
      Multiple hamartoma syndrome (Cowden’s disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma).
      ). Some early case reports suggest an increased risk for melanomas in individuals with PTEN variants (
      • Greene S.L.
      • Thomas J.R.
      • Doyle J.A.
      Cowden’s disease with associated malignant melanoma.
      ;
      • Reifenberger J.
      • Rauch L.
      • Beckmann M.W.
      • Megahed M.
      • Ruzicka T.
      • Reifenberger G.
      Cowden’s disease: clinical and molecular genetic findings in a patient with a novel PTEN germline mutation.
      ), although melanoma is not part of the diagnostic criteria for PHTS. More recently,
      • Innella G.
      • Bonora E.
      • Neri I.
      • Virdi A.
      • Guglielmo A.
      • Pradella L.M.
      • et al.
      PTEN hamartoma tumor syndrome: skin manifestations and insights into their molecular pathogenesis.
      identified an atypical mole/melanoma syndrome phenotype in patients with pathogenic PTEN variants containing a rare truncating sequence alteration (c.495G>A) in the CDH13 gene. The lifetime risk for acquiring melanoma is estimated at 6% (
      • Tan M.H.
      • Mester J.L.
      • Ngeow J.
      • Rybicki L.A.
      • Orloff M.S.
      • Eng C.
      • et al.
      Lifetime cancer risks in individuals with germline PTEN mutations.
      ), which is substantially less than the estimated risk for breast, thyroid, endometrial, colorectal, and kidney carcinomas. Although the evidence is limited, patients with pathogenic PTEN variants should undergo careful clinical evaluation (and if necessary, routine skin examinations) for adequate management of PHTS.

      TP53

      TP53 mutagenesis is one of the most frequently encountered events in cancer (
      • Olivier M.
      • Hollstein M.
      • Hainaut P.
      TP53 mutations in human cancers: origins, consequences, and clinical Use.
      ). Somatic TP53 variants occur in up to 19% of cutaneous melanoma cases (
      • Hodis E.
      • Watson I.R.
      • Kryukov G.V.
      • Arold S.T.
      • Imielinski M.
      • Theurillat J.-P.
      • et al.
      A landscape of driver mutations in melanoma.
      ). These somatic variants may occur through single-base substitution, loss of alleles, and inactivation by cellular or viral compounds (
      • Olivier M.
      • Hollstein M.
      • Hainaut P.
      TP53 mutations in human cancers: origins, consequences, and clinical Use.
      ). Germline variants of the TP53 gene cause Li‒Fraumeni syndrome (LFS), a rare cancer syndrome conferring a high lifetime risk for a wide range of cancers, including melanoma (Table 1). TP53 is a melanoma-promoting target of UV (
      • Hocker T.
      • Tsao H.
      Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants.
      ). Downregulation of HDM2 by p14ARF further suggests that p53 inactivation results from CDKN2A/p14ARF loss (
      • Kamijo T.
      • Weber J.D.
      • Zambetti G.
      • Zindy F.
      • Roussel M.F.
      • Sherr C.J.
      Functional and physical interactions of the ARF tumor suppressor with P53 and Mdm2.
      ). More recently, germline TP53 p.I254V variants causing p53 inactivation were found in two unrelated patients with UM (
      • Hajkova N.
      • Hojny J.
      • Nemejcova K.
      • Dundr P.
      • Ulrych J.
      • Jirsova K.
      • et al.
      Germline mutation in the TP53 gene in uveal melanoma.
      ). Approximately 70% of TP53 pathogenic variants in LFS arise as missense variants interspersed in six hotspot regions of the DNA-binding domain (
      • AlHarbi M.
      • Mubarak N.
      • AlMubarak L.
      • Aljelaify R.
      • AlSaeed M.
      • Almutairi A.
      • et al.
      Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family.
      ;
      • Leroy B.
      • Anderson M.
      • Soussi T.
      TP53 mutations in human cancer: database reassessment and prospects for the next decade.
      ). For such patients, routine skin examinations should be considered alongside interdisciplinary clinical management.

      Future Perspectives

      Gene, phenotype, and environmental interactions

      Penetrance of CKDN2A variants—ranging from 50 to 90%—appears to vary by geography and general population incidence rates, suggesting that factors that influence the general population also modify the risk with CKDN2A variants (
      • Bishop D.T.
      • Demenais F.
      • Goldstein A.M.
      • Bergman W.
      • Bishop J.N.
      • Bressac-de Paillerets B.
      • et al.
      Geographical variation in the penetrance of CDKN2A mutations for melanoma.
      ). Clearly, context matters, and gene‒gene and gene‒environment interactions continue to be studied in how specific variants may shape individual risk. Polygenic background is known to modify penetrance for monogenetic conditions (
      • Fahed A.C.
      • Wang Minxian
      • Homburger J.R.
      • Patel A.P.
      • Bick A.G.
      • Neben C.L.
      • et al.
      Polygenic background modifies penetrance of monogenic variants for Tier 1 genomic conditions.
      ). Among individuals with monogenetic variants, significant variation in disease penetrance has been associated with polygenic background. The probability of colon cancer by age 75 years ranged from 11 to 80% in individuals with a pathogenic Lynch syndrome sequence alteration. Similarly, the probability of developing breast cancer ranged from 13 to 76% for individuals with BRCA1 and BRCA2 variants on the basis of polygenic background (
      • Fahed A.C.
      • Wang Minxian
      • Homburger J.R.
      • Patel A.P.
      • Bick A.G.
      • Neben C.L.
      • et al.
      Polygenic background modifies penetrance of monogenic variants for Tier 1 genomic conditions.
      ). For individuals with CDKN2A variants, carrying MC1R variants has been associated with the diagnosis of melanoma at a younger age and the development of more melanomas than for those with CDKN2A variants alone (
      • Begg C.B.
      • Orlow I.
      • Hummer A.J.
      • Armstrong B.K.
      • Kricker A.
      • Marrett L.D.
      • et al.
      Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample.
      ;
      • Goldstein A.M.
      • Landi M.T.
      • Tsang S.
      • Fraser M.C.
      • Munroe D.J.
      • Tucker M.A.
      Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations.
      ). Developing a robust polygenic risk predictor to contextualize individual risk in those with MTS sequence variants may prove informative in counseling, screening, and prognostication.
      In addition to the interacting genetic background, environment may also substantially modify the penetrance of an MTS variant. For instance, among patients with CDKN2A variants, sun burns, increased sun exposure, and nevus phenotype have been associated with increased melanoma risk (
      • Chaudru V.
      • Chompret A.
      • Bressac-de Paillerets B.
      • Spatz A.
      • Avril M.-F.
      • Demenais F.
      Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families.
      ). Studies aimed to adequately describe gene‒environment interactions are limited and have been historically underpowered. In individuals with CDKN2A variants, activating NRAS variants were found in 95% of familial melanoma cases but in only 10% of sporadic melanomas (no reported family history of melanoma) (
      • Eskandarpour M.
      • Hashemi J.
      • Kanter L.
      • Ringborg U.
      • Platz A.
      • Hansson J.
      Frequency of UV-inducible NRAS mutations in melanomas of patients with germline CDKN2A mutations.
      ). These allelic variants were found both in primary melanomas and precancerous dysplastic nevi. The NRAS gene has previously been established as a target for UV-induced transformation, suggesting a possible hypermutability mechanism from this exposure (
      • Pierceall W.E.
      • Kripke M.L.
      • Ananthaswamy H.N.
      N-Ras mutation in ultraviolet radiation-induced murine skin cancers.
      ). Cultivating pooled databases across health and research institutions has the potential to allow for more robust comparisons and validation of existing studies. Moreover, natural language processing may be applied to electronic health records for phenotype and risk factor extraction. This information can then be coupled to gene prioritization algorithms to curate mechanistic associations (
      • Parikh J.R.
      • Genetti C.A.
      • Aykanat A.
      • Brownstein C.A.
      • Schmitz-Abe K.
      • Danowski M.
      • et al.
      A data-driven architecture using natural language processing to improve phenotyping efficiency and accelerate genetic diagnoses of rare disorders.
      ). Additional studies untangling the complex interaction between driver syndromic sequence variants in the context of other heritable traits and environmental exposures are needed.

      Multiomics approaches

      In more than half of melanoma cases clustered in families, a molecular predisposition for cancer has not been elucidated (
      • Goldstein A.M.
      • Chan M.
      • Harland M.
      • Gillanders E.M.
      • Hayward N.K.
      • Avril M.-F.
      • et al.
      High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.
      ) (Table 1). Recent progress in NGS has revolutionized the detection of causative genes in MTS that may be screened for in individual patients. In particular, NGS has elucidated previously underappreciated overlaps between melanoma-dominant tumor syndromes (i.e., those caused by CDK2NA or BAP1 alterations) and melanoma-associated tumor syndromes. However, there are numerous variants with an unknown significance of pathogenicity in familial melanoma cases that have yet to be classified. In 2017, a rare variant germline association study using whole-exome sequencing revealed strong signals in CDKN2A (P = 6.6 × 10‒8) and BAP1 (P = 3.83 × 10‒6) as well as in 11 borderline genes (P < 1 × 10‒4), including EBF3 (
      • Artomov M.
      • Stratigos A.J.
      • Kim I.
      • Kumar R.
      • Lauss M.
      • Reddy B.Y.
      • et al.
      Rare variant, gene-based association study of hereditary melanoma using whole-exome sequencing.
      ). More recently, whole-genome sequencing of a subset of acral melanomas revealed significant somatic variants in BRAF, NRAS, NF1, NOTCH2, PTEN, TYRP1, and KIT (
      • Newell F.
      • Wilmott J.S.
      • Johansson P.A.
      • Nones K.
      • Addala V.
      • Mukhopadhyay P.
      • et al.
      Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity.
      ). Variances in structural rearrangements and copy number signatures were also shown in TERT, CDK4, MDM2, CCND1, PAK1, and GAB2. These studies have identified the potential of NGS in the subclassification of melanoma and the identification of therapeutic targets.
      Given the missing heritable driver in half of familial melanoma cases, contributions from numerous low-risk, more common variants have been explored. A recent study explored the association of a 46 SNP polygenic risk score in explaining melanoma risk in Dutch patients with familial melanoma (
      • Potjer T.P.
      • van der Grinten TWJ
      • Lakeman I.M.M.
      • Bollen S.H.
      • Rodríguez-Girondo M.
      • Iles M.M.
      • et al.
      Association between a 46-SNP polygenic risk score and melanoma risk in Dutch patients with familial melanoma.
      ). Identifying and assembling contributing risk variants is an ongoing research effort. Large GWASs have identified 21 susceptibility loci for melanoma (
      • Ransohoff K.J.
      • Wu W.
      • Cho H.G.
      • Chahal H.C.
      • Lin Y.
      • Dai H.-J.
      • et al.
      Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.
      ). The contribution of rare yet significant coding variants remains understated in melanoma. Recent attempts at rare-variant gene-based association studies have identified additional melanoma susceptibility genes such as EBF3 (
      • Artomov M.
      • Stratigos A.J.
      • Kim I.
      • Kumar R.
      • Lauss M.
      • Reddy B.Y.
      • et al.
      Rare variant, gene-based association study of hereditary melanoma using whole-exome sequencing.
      ). When compared with canonical gene association studies (e.g., for common rather than rare variants), rare-variant studies require a targeted approach to enrich for pathogenic variants below a certain frequency threshold. Individual samples must be sequenced rather than genotyped using an existing set of cataloged sequence variants owing to a large number of potential variants. Once a rare-variant case is identified, the study requires aggregation of these samples into sets to examine frequency distribution against the control samples (
      • Zuk O.
      • Schaffner S.F.
      • Samocha K.
      • Do R.
      • Hechter E.
      • Kathiresan S.
      • et al.
      Searching for missing heritability: designing rare variant association studies.
      ). Another report analyzed the contribution of rare melanoma variants toward Parkinson’s disease using whole-exome sequencing data from 6,065 control and 6,875 Parkinson-positive samples. Parkinson's disease samples were found more likely than melanoma to harbor an unusually rare TYR p.V275F variant, although this finding had limited statistical power even after combining sets (
      • Lubbe S.J.
      • Escott-Price V.
      • Brice A.
      • Gasser T.
      • Pittman A.M.
      • Bras J.
      • et al.
      Rare variants analysis of cutaneous malignant melanoma genes in Parkinson’s disease.
      ). Rare-variant association studies may enable the discovery of previously undetected signals in the exome and enable more refined polygenic risk scores for melanoma.
      Epigenetic modifications—heritable changes in gene function that cannot be explained by changes in DNA sequence (
      • Felsenfeld G.
      A brief history of epigenetics.
      )—play a significant role in melanoma pathogenesis. For instance, PTEN promoter methylation has been associated as an independent predictor of impaired survival with patients with melanoma (
      • Roh M.R.
      • Gupta S.
      • Park K.H.
      • Chung K.Y.
      • Lauss M.
      • Flaherty K.T.
      • et al.
      Promoter methylation of PTEN is a significant prognostic factor in melanoma survival.
      ). Epigenetic alterations in germline inheritance have been reported in some familial cancer syndromes. Perhaps, the best described example is Lynch syndrome, which is canonically caused by germline variants in mismatch repair genes, including MLH1, MSH2, MSH6, PMS2, and EPCAM. In some families presenting with Lynch syndrome, no variants mutations in these genes could be identified. Rather, epigenetic silencing of MLH1 and MSH2 by DNA methylation in promoter regions was implicated (
      • Lee M.P.
      Understanding cancer through the lens of epigenetic inheritance, allele-specific gene expression, and high-throughput technology.
      ). To date, epimutations in CKDN2A have not been observed in familial melanoma (
      • Erlandson A.
      • Appelqvist F.
      • Enerbäck C.
      Epigenetic mutations in CDKN2A in Western Swedish families with hereditary malignant melanoma.
      ;
      • van Doorn R.
      • Zoutman W.H.
      • Gruis N.A.
      Absence of germline epimutation of the CDKN2A gene in familial melanoma.
      ). A more recent report analyzed five Dutch families, with at least three melanoma cases in different generations, for associated DNA methylation alterations. The authors concluded that despite several clustered epimutations discovered, these candidates were unlikely driving the predisposition (
      • Salgado C.
      • Gruis N.
      • Heijmans B.T.
      • Oosting J.
      • van Doorn R.
      BIOS Consortium
      Genome-wide analysis of constitutional DNA methylation in familial melanoma.
      ). Limitations of this study include the small number of families studied, and any causative epimutation may occur in a subset of melanoma families (and unlikely to be common in all). In addition, samples were interrogated on a 450K Illumina array that interrogated the methylation status of CpG sites in all gene promoters but did not cover other possible regulatory sequences (
      • Salgado C.
      • Gruis N.
      • Heijmans B.T.
      • Oosting J.
      • van Doorn R.
      BIOS Consortium
      Genome-wide analysis of constitutional DNA methylation in familial melanoma.
      ). Future research focused on additional epigenetic mechanisms, including noncoding RNA, will continue to help elucidate unexplained predisposition to hereditary melanoma.

      Precision medicine

      Current guidelines for genetic testing in melanoma are restricted to CDK2NA screening and employ the rule of twos, threes, and fours (
      • Delaunay J.
      • Martin L.
      • Bressac-de Paillerets B.
      • Duru G.
      • Ingster O.
      • Thomas L.
      Improvement of genetic testing for cutaneous melanoma in countries with low to moderate incidence: the rule of 2 vs the rule of 3.
      ). According to this rule, genetic testing is indicated for subjects with ≥2, ≥3, or ≥4 primary melanomas or genetically related cancers depending on the general population incidence. Penetrance of CDKN2A variants may be influenced by intense and intermittent UV exposure in conjunction with certain high-risk phenotypes—such as pale skin, tanning ability, and red hair color. Therefore, regional context may be used to supplement the rule of twos, threes, and fours (
      • Leachman S.A.
      • Carucci J.
      • Kohlmann W.
      • Banks K.C.
      • Asgari M.M.
      • Bergman W.
      • et al.
      Selection criteria for genetic assessment of patients with familial melanoma.
      ). Regions with low background incidence may consider two instances of melanoma or PC in first- or second-degree relatives to qualify for a genetic referral. In contrast, a moderate-to-high background incidence may require three or more instances of disease. In families with no detectable CDKN2A variant, gene panel testing that includes CDK4 testing should be considered (
      • Leachman S.A.
      • Lucero O.M.
      • Sampson J.E.
      • Cassidy P.
      • Bruno W.
      • Queirolo P.
      • et al.
      Identification, genetic testing, and management of hereditary melanoma.
      ). Furthermore, clinical prediction algorithms such as MELPREDICT (
      • Niendorf K.B.
      • Goggins W.
      • Yang G.
      • Tsai K.Y.
      • Shennan M.
      • Bell D.W.
      • et al.
      MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability.
      ;
      • Taylor N.J.
      • Mitra N.
      • Qian L.
      • Avril M.F.
      • Bishop D.T.
      • Bressac-de Paillerets B.
      • et al.
      Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.
      ) and MelaPRO (
      • Wang W.
      • Niendorf K.B.
      • Patel D.
      • Blackford A.
      • Marroni F.
      • Sober A.J.
      • et al.
      Estimating CDKN2A carrier probability and personalizing cancer risk assessments in hereditary melanoma using MelaPRO.
      ) may be useful for estimating the presence of a CDK2NA variant and overall melanoma risk.
      To our knowledge, there are more than 20 commercial laboratories that offer NGS panels, which include genes implicated in hereditary melanoma. The genes included on these panels may vary, but most typically include BAP2, BRCA2, CDK4, CDKN2A, MITF (E318K), POT1, PTEN, RB1, and TP53. Genetic testing should therefore be ordered by specialists who can select the most appropriate laboratory test. Providers must obtain informed consent before ordering genetic testing, a process that requires adequate education related to the risks and benefits of genetic testing, potential outcomes of testing, and implications for both the patient and family members. Interpretation of test results should be done in the context of the patient’s personal and family history of cancer so that appropriate medical management guidance can be provided in the event of positive, negative, and uncertain test results. Testing in commercial laboratories typically includes multigene panel testing as long as criteria are met for CDKN2A. Most laboratories preform insurance preauthorization before running clinical testing. In most cases, commercial insurance will cover the cost of genetic testing even if no insurance criteria exist for CDKN2A. Out-of-pocket costs for gene panel testing are now approximately $250 in many laboratories, which has significantly removed the financial barrier of these tests.
      Total body surveillance is an important component of clinical management in patients predisposed to melanoma. Image-based diagnostics such as deep neural networks have enabled rapid diagnosis and triaging of skin cancer (
      • Esteva A.
      • Kuprel B.
      • Novoa R.A.
      • Ko J.
      • Swetter S.M.
      • Blau H.M.
      • et al.
      Dermatologist-level classification of skin cancer with deep neural networks.
      ;
      • Tschandl P.
      • Rinner C.
      • Apalla Z.
      • Argenziano G.
      • Codella N.
      • Halpern A.
      • et al.
      Human–computer collaboration for skin cancer recognition.
      ). Full-body imaging (or three-dimensional imaging) is an emerging technique for patients predisposed to numerous atypical pigmented lesions, a previous diagnosis of melanoma, or a positive family history of melanoma. The apparatus catalogs an interactive image of the patient’s skin using an array of cameras integrated with software. Such technology may be used to monitor the onset and development of dysplastic nevi, which presents an increased risk for melanoma. Acquired nevi often serve as precursors to these lesions, although they are most commonly benign (
      • Elder D.E.
      Precursors to melanoma and their mimics: nevi of special sites.
      ). These lesions exhibit a dynamic life cycle containing the following stages: inception, growth, senescence, and involution (
      • Terushkin V.
      • Scope A.
      • Halpern A.C.
      • Marghoob A.A.
      Pathways to involution of nevi: insights from dermoscopic follow-up.
      ). Inception occurs when a nevus progenitor cell acquires a sequence alteration to facilitate proliferation. Growth defines active nevus proliferation. Senescence involves a series of cellular brakes that stop proliferation. Nevi are then relatively stable for a period of time before the lesion regresses and eventually disappears (
      • Ross A.L.
      • Sanchez M.I.
      • Grichnik J.M.
      ).
      A previous cohort study determined that patients at risk for melanoma underwent significantly fewer biopsies after full-body imaging (
      • Truong A.
      • Strazzulla L.
      • March J.
      • Boucher K.M.
      • Nelson K.C.
      • Kim C.C.
      • et al.
      Reduction in nevus biopsies in patients monitored by total body photography.
      ). Younger patients were found to have higher rates of biopsy, suggesting that full-body imaging may be less effective in those with increasing or changing nevi (
      • Rayner J.E.
      • Laino A.M.
      • Nufer K.L.
      • Adams L.
      • Raphael A.P.
      • Menzies S.W.
      • et al.
      Clinical perspective of 3D total body photography for early detection and screening of melanoma.
      ;
      • Truong A.
      • Strazzulla L.
      • March J.
      • Boucher K.M.
      • Nelson K.C.
      • Kim C.C.
      • et al.
      Reduction in nevus biopsies in patients monitored by total body photography.
      ). These digital skin models can be easily accessed by either the patient or dermatologist during follow-up, thereby increasing the potential to reinforce self-surveillance behaviors. Furthermore, full-body imaging may also enable the early detection of lesions specific to MTSs, for example, in BAP1 tumor disposition syndrome. Patients with this disorder may uniquely present with reddish‒brown and dome-shaped papules that are 2‒10 mm in diameter (
      • Soura E.
      • Eliades P.J.
      • Shannon K.
      • Stratigos A.J.
      • Tsao H.
      Hereditary melanoma: update on syndromes and management: emerging melanoma cancer complexes and genetic counseling.
      ). Computerized magnification may also enable the detection of BAP1-mutated atypical intradermal tumors on the basis of histological features. Further studies that compare the appearance of nevi associated with MTSs with those associated with sporadic tumors are required. Altogether, clinical guidelines for skin surveillance—regardless of technology—should be routinely monitored to reflect our collective knowledge of the disease.

      Conclusion

      Over the past few decades, tremendous strides have been made in the field of MTS. Early linkage attempts to decipher familial clusters resulted in the discovery of melanomas enriched in families with pathogenic CDKN2A and CD4 allelic variants. Since then, our understanding of heritable melanoma has been enriched with a more nuanced understanding of genetic and environmental context. In the era of personalized medicine, a more refined understanding of how high-risk sequence alterations interact with polygenic backgrounds and environmental exposures can help clinicians to deliver patient-centered, risk-stratified care.

      Data availability statement

      No datasets were generated or analyzed during this study.

      Conflict of Interest

      SRM and HT are authors of the chapter, “Inherited susceptibility to melanoma” in UpToDate. The remaining authors state no conflict of interest.

      Author Contributions

      Conceptualization: SR, SG, HT; Writing - Original Draft Preparation: SR, SG, SRM, HT; Writing - Review and Editing: SR, SG, SRM, HT

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