Schadendorf Dirk,Fisher David E,Garbe Claus,Gershenwald Jeffrey E,Grob Jean-Jacques,Halpern Allan,Herlyn Meenhard,Marchetti Michael A,McArthur Grant,Ribas Antoni,Roesch Alexander,Hauschild Axel
Nature reviews. Disease primers
Melanoma is a common cancer in the Western world with an increasing incidence. Sun exposure is still considered to be the major risk factor for melanoma. The prognosis of patients with malignant (advanced-stage) melanoma differs widely between countries, but public campaigns advocating early detection have led to significant reductions in mortality rates. As well as sun exposure, distinct genetic alterations have been identified as associated with melanoma. For example, families with melanoma who have germline mutations in CDKN2A are well known, whereas the vast majority of sporadic melanomas have mutations in the mitogen-activated protein kinase cascade, which is the pathway with the highest oncogenic and therapeutic relevance for this disease. BRAF and NRAS mutations are typically found in cutaneous melanomas, whereas KIT mutations are predominantly observed in mucosal and acral melanomas. GNAQ and GNA11 mutations prevail in uveal melanomas. Additionally, the PI3K-AKT-PTEN pathway and the immune checkpoint pathways are important. The finding that programmed cell death protein 1 ligand 1 (PDL1) and PDL2 are expressed by melanoma cells, T cells, B cells and natural killer cells led to the recent development of programmed cell death protein 1 (PD1)-specific antibodies (for example, nivolumab and pembrolizumab). Alongside other new drugs - namely, BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitors (trametinib and cobimetinib) - these agents are very promising and have been shown to significantly improve prognosis for patients with advanced-stage metastatic disease. Early signs are apparent that these new treatment modalities are also improving long-term clinical benefit and the quality of life of patients. This Primer summarizes the current understanding of melanoma, from mechanistic insights to clinical progress. For an illustrated summary of this Primer, visit: http://go.nature.com/vX2N9s.
Rare SF3B1 R625 mutations in cutaneous melanoma.
Kong Yong,Krauthammer Michael,Halaban Ruth
RNA splicing is the cellular process that has only recently been found to be an important target for various cancers. Among the spliceosome genes that are involved in cancers, SF3B1 is most frequently mutated. Recurrent mutation in codon 625 has been found in uveal melanoma, but this mutation has not been identified in cutaneous melanoma. We used whole-exome sequencing to explore the mutational landscape of 295 melanoma samples, 231 of which are cutaneous melanoma. Among these cutaneous melanoma samples, we found two samples with R625 mutation in SF3B1 gene. The results were validated by Sanger sequencing. We conclude that SF3B1 R625 mutation does occur in cutaneous melanoma, although with a low frequency (∼1%).
SF3B1 and BAP1 mutations in blue nevus-like melanoma.
Griewank Klaus G,Müller Hansgeorg,Jackett Louise A,Emberger Michael,Möller Inga,van de Nes Johannes Ap,Zimmer Lisa,Livingstone Elisabeth,Wiesner Thomas,Scholz Simone L,Cosgarea Ioana,Sucker Antje,Schimming Tobias,Hillen Uwe,Schilling Bastian,Paschen Annette,Reis Henning,Mentzel Thomas,Kutzner Heinz,Rütten Arno,Murali Rajmohan,Scolyer Richard A,Schadendorf Dirk
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
Blue nevi are melanocytic tumors originating in the cutaneous dermis. Malignant tumors may arise in association with or resembling blue nevi, so called 'blue nevus-like melanoma', which can metastasize and result in patient death. Identifying which tumors will behave in a clinically aggressive manner can be challenging. Identifying genetic alterations in such tumors may assist in their diagnosis and prognostication. Blue nevi are known to be genetically related to uveal melanomas (eg, both harboring GNAQ and GNA11 mutations). In this study, we analyzed a large cohort (n=301) of various morphologic variants of blue nevi and related tumors including tumors diagnosed as atypical blue nevi (n=21), and blue nevus-like melanoma (n=12), screening for all gene mutations known to occur in uveal melanoma. Similar to published reports, we found the majority of blue nevi harbored activating mutations in GNAQ (53%) or GNA11 (15%). In addition, rare CYSLTR2 (1%) and PLCB4 (1%) mutations were identified. EIF1AX, SF3B1, and BAP1 mutations were also detected, with BAP1 and SF3B1 R625 mutations being present only in clearly malignant tumors (17% (n=2) and 25% (n=3) of blue nevus-like melanoma, respectively). In sequencing data from a larger cohort of cutaneous melanomas, this genetic profile was also identified in tumors not originally diagnosed as blue nevus-like melanoma. Our findings suggest that the genetic profile of coexistent GNAQ or GNA11 mutations with BAP1 or SF3B1 mutations can aid the histopathological diagnosis of blue nevus-like melanoma and distinguish blue nevus-like melanoma from conventional epidermal-derived melanomas. Future studies will need to further elucidate the prognostic implications and appropriate clinical management for patients with tumors harboring these mutation profiles.
Whole-genome landscapes of major melanoma subtypes.
Hayward Nicholas K,Wilmott James S,Waddell Nicola,Johansson Peter A,Field Matthew A,Nones Katia,Patch Ann-Marie,Kakavand Hojabr,Alexandrov Ludmil B,Burke Hazel,Jakrot Valerie,Kazakoff Stephen,Holmes Oliver,Leonard Conrad,Sabarinathan Radhakrishnan,Mularoni Loris,Wood Scott,Xu Qinying,Waddell Nick,Tembe Varsha,Pupo Gulietta M,De Paoli-Iseppi Ricardo,Vilain Ricardo E,Shang Ping,Lau Loretta M S,Dagg Rebecca A,Schramm Sarah-Jane,Pritchard Antonia,Dutton-Regester Ken,Newell Felicity,Fitzgerald Anna,Shang Catherine A,Grimmond Sean M,Pickett Hilda A,Yang Jean Y,Stretch Jonathan R,Behren Andreas,Kefford Richard F,Hersey Peter,Long Georgina V,Cebon Jonathan,Shackleton Mark,Spillane Andrew J,Saw Robyn P M,López-Bigas Núria,Pearson John V,Thompson John F,Scolyer Richard A,Mann Graham J
Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.
Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets.
Newell Felicity,Kong Yan,Wilmott James S,Johansson Peter A,Ferguson Peter M,Cui Chuanliang,Li Zhongwu,Kazakoff Stephen H,Burke Hazel,Dodds Tristan J,Patch Ann-Marie,Nones Katia,Tembe Varsha,Shang Ping,van der Weyden Louise,Wong Kim,Holmes Oliver,Lo Serigne,Leonard Conrad,Wood Scott,Xu Qinying,Rawson Robert V,Mukhopadhyay Pamela,Dummer Reinhard,Levesque Mitchell P,Jönsson Göran,Wang Xuan,Yeh Iwei,Wu Hong,Joseph Nancy,Bastian Boris C,Long Georgina V,Spillane Andrew J,Shannon Kerwin F,Thompson John F,Saw Robyn P M,Adams David J,Si Lu,Pearson John V,Hayward Nicholas K,Waddell Nicola,Mann Graham J,Guo Jun,Scolyer Richard A
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.
An unholy alliance: cooperation between BRAF and NF1 in melanoma development and BRAF inhibitor resistance.
Gibney Geoffrey T,Smalley Keiran S M
In this issue of Cancer Discovery, 2 studies provide new evidence implicating loss of the tumor suppressor neurofibromin (NF1) in the biologic behavior of cutaneous melanoma. The first study from Maertens and colleagues describes a new transgenic mouse model in which mutant BRAF cooperates with NF1 loss to drive melanoma development through the abrogation of oncogene-induced senescence. The second, from Whittaker and colleagues, used a high-throughput short hairpin RNA screening approach to identify NF1 loss as a key mediator of acquired and intrinsic BRAF inhibitor resistance. Together these studies provide new insights into the signaling that underlies melanoma initiation and progression and suggests novel therapeutic strategies for patients whose melanomas are BRAF-mutant/NF1-deficient.
KIT, NRAS and BRAF mutations in sinonasal mucosal melanoma: a study of 56 cases.
Zebary A,Jangard M,Omholt K,Ragnarsson-Olding B,Hansson J
British journal of cancer
BACKGROUND:Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs. METHODS:Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing. RESULTS:Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027). CONCLUSION:Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.
Natural melanoma-derived extracellular vesicles.
Hood Joshua L
Seminars in cancer biology
Melanoma cells produce a variety of extracellular vesicle (EV) types including shedding vesicles and exosomes (EXOs). These EVs are defined by their mechanism of cellular production. To date, the majority of EV investigations has centered around melanoma EXOs or small EVs (sEVs). Natural melanoma sEVs mediate pro-tumor processes including angiogenesis, immune regulation and modification of tissue microenvironments. A thorough examination of these processes reveals that they are interdependent. They work in concert to support tumor growth and survival. Pro-tumor functions attributed to melanoma cells are reproduced by melanoma sEVs. This ensures a certain degree of redundancy within the melanoma pathogenic process. It also allows for rapid adaptation of melanoma cells to changing microenvironments, anti-tumor immune responses, and therapeutic challenges. Further, as a result of their composition and inherent ability to engage the immune system, natural melanoma EVs possess excellent biomarker potential and might be used therapeutically as tumor vaccines.
Neuro-immune regulation of mucosal physiology.
Chesné Julie,Cardoso Vânia,Veiga-Fernandes Henrique
Mucosal barriers constitute major body surfaces that are in constant contact with the external environment. Mucosal sites are densely populated by a myriad of distinct neurons and immune cell types that sense, integrate and respond to multiple environmental cues. In the recent past, neuro-immune interactions have been reported to play central roles in mucosal health and disease, including chronic inflammatory conditions, allergy and infectious diseases. Discrete neuro-immune cell units act as building blocks of this bidirectional multi-tissue cross-talk, ensuring mucosal tissue health and integrity. Herein, we will focus on reciprocal neuro-immune interactions in the airways and intestine. Such neuro-immune cross-talk maximizes sensing and integration of environmental aggressions, which can be considered an important paradigm shift in our current views of mucosal physiology and immune regulation.
Mucosal melanoma: a clinically and biologically unique disease entity.
Carvajal Richard D,Spencer Sharon A,Lydiatt William
Journal of the National Comprehensive Cancer Network : JNCCN
Mucosal melanoma (MM) is an aggressive and clinically complex malignancy made more challenging by its relative rarity. Because of the rarity of MM as a whole, and because of the unique biology and clinical challenges of MM arising from each anatomic location, understanding of this disease and its optimal management remains limited. The impact of various treatment strategies on disease control and survival has been difficult to assess because of the small size of most reported series of MM arising from any one particular site, the retrospective nature of most series, and the lack of a uniform comprehensive staging system for this disease. This article summarizes the clinical, pathologic, and molecular features, and the diagnostic and therapeutic considerations for the management of MM, underscoring the similarities and differences from cutaneous melanoma. Furthermore, the distinct clinical features and management implications unique to melanoma arising from the mucosal surfaces of the head and neck, the anorectal region, and the female genital tract are highlighted.
Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma.
Furney Simon J,Turajlic Samra,Stamp Gordon,Nohadani Mahrokh,Carlisle Anna,Thomas J Meirion,Hayes Andrew,Strauss Dirk,Gore Martin,van den Oord Joost,Larkin James,Marais Richard
The Journal of pathology
Mucosal melanoma displays distinct clinical and epidemiological features compared to cutaneous melanoma. Here we used whole genome and whole exome sequencing to characterize the somatic alterations and mutation spectra in the genomes of ten mucosal melanomas. We observed somatic mutation rates that are considerably lower than occur in sun-exposed cutaneous melanoma, but comparable to the rates seen in cancers not associated with exposure to known mutagens. In particular, the mutation signatures are not indicative of ultraviolet light- or tobacco smoke-induced DNA damage. Genes previously reported as mutated in other cancers were also mutated in mucosal melanoma. Notably, there were substantially more copy number and structural variations in mucosal melanoma than have been reported in cutaneous melanoma. Thus, mucosal and cutaneous melanomas are distinct diseases with discrete genetic features. Our data suggest that different mechanisms underlie the genesis of these diseases and that structural variations play a more important role in mucosal than in cutaneous melanomagenesis.
Mucosal melanoma of the head and neck: a systematic review of the literature.
Lazarev Stanislav,Gupta Vishal,Hu Kenneth,Harrison Louis B,Bakst Richard
International journal of radiation oncology, biology, physics
Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN.
Tumor Mutation Burden and Structural Chromosomal Aberrations Are Not Associated with T-cell Density or Patient Survival in Acral, Mucosal, and Cutaneous Melanomas.
Edwards Jarem,Ferguson Peter M,Lo Serigne N,Pires da Silva Inês,Colebatch Andrew J,Lee Hansol,Saw Robyn P M,Thompson John F,Menzies Alexander M,Long Georgina V,Newell Felicity,Pearson John V,Waddell Nicola,Hayward Nicholas K,Johansson Peter A,Mann Graham J,Scolyer Richard A,Palendira Umaimainthan,Wilmott James S
Cancer immunology research
Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous melanoma subtypes, which are known to have different TMB. It is also unknown whether chromosomal structural mutations [structural variant (SV) mutations] contribute to the immunogenicity in acral and mucosal melanomas where such aberrations are common. We stained 151 cutaneous and 35 acral and mucosal melanoma patient samples using quantitative IHC and correlated immune infiltrate phenotypes with TMB and other genomic profiles. TMB and SVs did not correlate with the densities of CD8 lymphocytes, CD103 tumor-resident T cells (Trm), CD45RO cells, and other innate and adaptive immune cell subsets in cutaneous and acral/mucosal melanoma tumors, respectively, including in analyses restricted to the site of disease and in a validation cohort. In 43 patients with stage III treatment-naïve cutaneous melanoma, we found that the density of immune cells, particularly Trm, was significantly associated with patient survival, but not with TMB. Overall, TMB and chromosomal structural aberrations are not associated with protective antitumor immunity in treatment-naïve melanoma.
Update on primary mucosal melanoma.
Tacastacas Joselin D,Bray Julie,Cohen Yoon K,Arbesman Joshua,Kim Julian,Koon Henry B,Honda Kord,Cooper Kevin D,Gerstenblith Meg R
Journal of the American Academy of Dermatology
Mucosal melanomas are aggressive cancers of mucosal surfaces with clinical and pathologic characteristics distinct from cutaneous melanomas, warranting different staging systems and treatment approaches. Surgical resection is performed frequently for the primary tumor, although the utility of lymph node surgery and radiation therapy is not established. Therapies targeted against C-KIT activating mutations, identified in many mucosal melanomas, are emerging as promising treatments.
Mucosal melanoma of the head and neck.
Ascierto Paolo Antonio,Accorona Remo,Botti Gerardo,Farina Davide,Fossati Piero,Gatta Gemma,Gogas Helen,Lombardi Davide,Maroldi Roberto,Nicolai Piero,Ravanelli Marco,Vanella Vito
Critical reviews in oncology/hematology
Mucosal melanoma of the head and neck is a very rare and aggressive malignancy with a very poor prognosis. The nasal cavity, paranasal sinuses, and oral cavity are the most common locations. One-, 3- and 5-year survival rates between 2000 and 2007 were 63%, 30% and 20%, respectively. Cigarette smoking seems to be a risk factor even though the evidence for this is very low. Clinical signs and symptoms are usually nonspecific. While surgery is considered the mainstay of treatment for most mucosal melanomas of the head and neck region, radiotherapy has a role in local control of the disease after surgery. Many new treatment options in the last years, in particular targeted therapies (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) and immunotherapies (anti CTLA-4 and anti PD-1/PD-L1 antibodies), have changed the history of cutaneous melanoma. Despite the different biology, mucosal melanoma is currently treated in the same way as cutaneous melanoma; however, patients with mucosal melanoma were excluded from the majority of recent clinical trials. Recent molecular findings offer new hope for the development of more effective systemic therapy.
KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development.
Meng Da,Carvajal Richard D
American journal of clinical dermatology
Metastatic melanoma is a heterogenous disease that has served as a model for the development of both targeted therapy and immunotherapy. KIT-mutated melanoma represents a rare subset, most commonly arising from acral, mucosal, and chronically sun-damaged skin. Additionally, KIT alterations are enriched in the triple wild-type subtype of cutaneous melanoma. Activating alterations of KIT-a transmembrane receptor tyrosine kinase important for cell development, growth, and differentiation-have been shown to be critical to oncogenesis across many tumor subtypes. Following the successes of BRAF-targeted therapy in melanoma and KIT-targeted therapy in gastrointestinal stromal tumors, small-molecule tyrosine kinase inhibitors targeting KIT have been examined in KIT-mutated melanoma. KIT inhibitors that have been investigated in relevant clinical trials in advanced melanoma include imatinib, sunitinib, dasatinib, and nilotinib. In these studies, selected patients with KIT-mutated melanoma were shown to be responsive to therapy with KIT inhibition, especially patients with L576P and K642E mutations. This has led to the incorporation of KIT-targeted therapy in the National Comprehensive Cancer Network guidelines for systemic therapy for metastatic or unresectable melanoma. Current research and development efforts include novel KIT-targeted therapies and testing KIT inhibitors in combination with immunotherapy.
Genome-wide analysis of canine oral malignant melanoma metastasis-associated gene expression.
Bowlt Blacklock K L,Birand Z,Selmic L E,Nelissen P,Murphy S,Blackwood L,Bass J,McKay J,Fox R,Beaver S,Starkey M
Oral malignant melanoma (OMM) is the most common canine melanocytic neoplasm. Overlap between the somatic mutation profiles of canine OMM and human mucosal melanomas suggest a shared UV-independent molecular aetiology. In common with human mucosal melanomas, most canine OMM metastasise. There is no reliable means of predicting canine OMM metastasis, and systemic therapies for metastatic disease are largely palliative. Herein, we employed exon microarrays for comparative expression profiling of FFPE biopsies of 18 primary canine OMM that metastasised and 10 primary OMM that did not metastasise. Genes displaying metastasis-associated expression may be targets for anti-metastasis treatments, and biomarkers of OMM metastasis. Reduced expression of CXCL12 in the metastasising OMMs implies that the CXCR4/CXCL12 axis may be involved in OMM metastasis. Increased expression of APOBEC3A in the metastasising OMMs may indicate APOBEC3A-induced double-strand DNA breaks and pro-metastatic hypermutation. DNA double strand breakage triggers the DNA damage response network and two Fanconi anaemia DNA repair pathway members showed elevated expression in the metastasising OMMs. Cross-validation was employed to test a Linear Discriminant Analysis classifier based upon the RT-qPCR-measured expression levels of CXCL12, APOBEC3A and RPL29. Classification accuracies of 94% (metastasising OMMs) and 86% (non-metastasising OMMs) were estimated.
Dermoscopic appearance of an amelanotic mucosal melanoma.
Blum Andreas,Beck-Zoul Ulrike,Held Laura,Haase Sylvie
Dermatology practical & conceptual
BACKGROUND:Hypomelanotic or amelanotic melanomas are challenging to identify, especially at mucosal sites. The dermoscopic clues to the diagnosis of mucosal melanomas have been reported to be structureless zones with the presence of blue, gray, or white colors. CASE:A female in her seventies noted a new lesion on the inside of her right labia that first appeared two months prior. Her past medical history was significant for rheumatoid arthritis requiring ongoing treatment with methotrexate for 20 years and adalimumab for 10 years. After no response to two weeks of local treatment for suspected herpes simplex infection, her gynecologist performed a skin biopsy. Based on the histopathological diagnosis of an amelanotic melanoma (Breslow thickness of 1.3 mm) the patient was referred to dermatology for further assessment. Polarized dermoscopy revealed a distinct asymmetric, sharply demarcated homogenous white papule (4 × 5 mm) as well as polymorphous vessels. CONCLUSION:Dermoscopy may aid in the diagnosis of amelanotic mucosal melanomas. Our case revealed a structureless white area and polymorphous vessels. Additional clues to the diagnosis were the advanced age of the patient and the clinical presentation of a new lesion.
In Vivo Reflectance Confocal Microscopy for the Diagnosis of Melanoma and Melanotic Macules of the Lip.
Uribe Pablo,Collgros Helena,Scolyer Richard A,Menzies Scott W,Guitera Pascale
Importance:Benign melanotic macules (MAC) are the most frequent cause of lip pigmentation and sometimes difficult to differentiate from lip melanoma (MEL). Objectives:To report in vivo reflectance confocal microscopy (RCM) features of normal lips of different phototypes and to identify features that assist in distinguishing MEL from MAC using dermoscopy and RCM. Design, Setting, and Participants:For this retrospective observational study, 2 groups of patients from 2 tertiary referral centers for melanoma (Sydney Melanoma Diagnostic Centre and Melanoma Institute Australia) were recruited between June 2007 and January 2015. Group 1 included patients with normal lips and different phototypes, and Group 2 consisted of patients with MAC and MEL; RCM and dermoscopy were used for lips analysis. Main Outcomes and Measures:Overall, 92 RCM features were correlated with clinical history, dermoscopic images, and histopathology in all patients with MEL and 5 patients with MAC. Results:Images from the vermillion and/or mucosal part of the lip were recorded from 10 patients with clinically normal lips (mean [SD] age, 34.5 [6.1] years), 16 patients with MAC (mean [SD] age, 49.6 [17.9] years), and 5 patients with 6 cases of MEL (1 patient had a recurrent lesion; mean [SD] age, 56.2 [15.5] years). In normal lips, the draped pattern-a previously described MAC RCM feature-was identified in all cases. In MEL, the following findings were frequent and significantly different from MAC: epidermal disarray; pagetoid infiltration of dendritic and/or round cells; a nonspecific architectural pattern at the dermoepidermal junction (DEJ); nonhomogenously distributed papillae; continuous (lentiginous) proliferation of cells with marked atypia at the DEJ, especially in interpapillary spaces; a higher number of dendritic cells (especially roundish); and atypical round cells at the DEJ. The cellular body area of dendritic cells was about the double in MEL compared with MAC. An RCM lip algorithm was developed that provided 100% sensitivity and 88% specificity for the diagnosis of MEL of the vermillion and mucosal part of the lip. With dermoscopy, MAC were correctly classified as benign in 13 of 16 cases (81%) and MEL were classified as equivocal or malignant in 5 of 6 cases (83%). Conclusions and Relevance:Reflectance confocal microscopy can assist in the differential diagnosis of lip MEL and MAC. An RCM Lip Score that we developed based on study results is proposed and needs to be validated on an independent data set.
A case report of disappearing pigmented skin lesions associated with pembrolizumab treatment for metastatic melanoma.
Wolner Z J,Marghoob A A,Pulitzer M P,Postow M A,Marchetti M A
The British journal of dermatology
Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death (PD)-1 receptor. Common cutaneous adverse side-effects of PD-1 inhibitors include maculopapular rash, pruritus, vitiligo and lichenoid skin and mucosal reactions. Here we describe a man in his sixties with metastatic melanoma treated with pembrolizumab who subsequently developed fading or disappearance of pigmented skin lesions, lightening of the skin, and poliosis of the eyebrows, eyelashes and scalp and body hair. Compared with baseline high-resolution three-dimensional total-body photography, we observed fading or disappearance of solar lentigines, seborrhoeic keratoses and melanocytic naevi, suggesting that PD-1 inhibitors may affect the evolution of these benign skin lesions. With dermatoscopic follow-up, altered lesions showed either blue-grey peppering/granularity or fading in colour without other identifiable features. No halo lesions or lesions with surrounding inflammation were identified. One changed pigmented lesion that showed blue-grey peppering/granularity on dermoscopy was biopsied and interpreted as a macular seborrhoeic keratosis with melanophages. Further studies are required to elucidate the effects of PD-1 inhibition on benign skin lesions.
KIT Suppresses BRAF-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling.
Neiswender James V,Kortum Robert L,Bourque Caitlin,Kasheta Melissa,Zon Leonard I,Morrison Deborah K,Ceol Craig J
The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF- or NRAS-activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a mutation into a strain of melanoma-prone zebrafish. Melanoma onset was accelerated in fish. Tumors from animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAF-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAF could paradoxically reduce signaling downstream of BRAF, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAF signaling. , expression of wild-type BRAF delayed melanoma onset, but only in a -dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAF-driven melanoma formation. .
Pathway and Promoter Gene Mutation Pattern and Its Prognostic Value in Melanoma Patients: A Retrospective Study of 2,793 Cases.
Bai Xue,Kong Yan,Chi Zhihong,Sheng Xinan,Cui Chuanliang,Wang Xuan,Mao Lili,Tang Bixia,Li Siming,Lian Bin,Yan Xieqiao,Zhou Li,Dai Jie,Guo Jun,Si Lu
Clinical cancer research : an official journal of the American Association for Cancer Research
Ethnic differences are conspicuous in melanoma. This study is to obtain a comprehensive view of a genomic landscape and a better understanding of the correlations of gene mutation status with clinicopathologic characteristics and disease prognosis in the Asian population. A total of 2,793 melanoma patient samples were retrospectively collected and analyzed for mutations in C-KIT, BRAF, NRAS, and PDGFRA coding regions and telomerase reverse transcriptase (TERT) promoter region by Sanger sequencing. Mutations were correlated to clinicopathologic features and overall survival. The incidences of somatic mutations within the BRAF, NRAS, C-KIT, TERT-228, TERT-250, and PDGFRA genes were 23.7%, 10.4%, 8.0%, 5.9%, 5.5%, and 1.4%, respectively. Hotspot mutations accounted for 95.8% and 87.2% of BRAF and NRAS mutations, respectively; meanwhile, C-KIT and PDGFRA mutations showed more heterogeneity. BRAF, C-KIT, and NRAS mutations were mutually exclusive. BRAF, C-KIT, NRAS, and numbers of gene mutations of the MAPK pathway were all independent negative prognostic factors ( = 0.007, other < 0.001, respectively). In acral melanoma, BRAF, C-KIT, and NRAS mutations were all independent prognostic factors of worse overall survival (all < 0.001), whereas in mucosal melanoma, only C-KIT was ( = 0.006). Although correlated with BRAF mutations ( = 0.001 and < 0.001 for C228T and C250T, respectively), TERT promoter gene mutations were not correlated with overall survival ( = 0.406 and 0.256, respectively). The MAPK pathway and TERT promoter gene mutations are differentially represented in the Asian population. Mutations in BRAF, C-KIT, and NRAS have prognostic values that vary by melanoma subtypes. Clinical treatment targeting these critical pathways should be aimed directly at these poor-prognosis subpopulations for maximum potential impact. .
MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma.
Zhan Yao,Guo Jun,Yang William,Goncalves Christophe,Rzymski Tomasz,Dreas Agnieszka,Żyłkiewicz Eliza,Mikulski Maciej,Brzózka Krzysztof,Golas Aniela,Kong Yan,Ma Meng,Huang Fan,Huor Bonnie,Guo Qianyu,da Silva Sabrina Daniela,Torres Jose,Cai Yutian,Topisirovic Ivan,Su Jie,Bijian Krikor,Alaoui-Jamali Moulay A,Huang Sidong,Journe Fabrice,Ghanem Ghanem E,Miller Wilson H,Del Rincón Sonia V
The Journal of clinical investigation
Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase-interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.
Distinct MAPK and PI3K pathway mutations in different melanoma types in Taiwanese individuals.
Gao Hong-Wei,Tsai Wen-Chiuan,Perng Cherng-Lih,Wang Wei-Ming,Chiang Chien-Ping
European journal of dermatology : EJD
BACKGROUND:A number of studies investigating mutations of genes involved in MAPK and PI3K pathways in melanoma patients have been performed, most of which were based on Caucasian populations. OBJECTIVES:We sought to identify BRAF, NRAS, MEK1, PI3K, and PTEN mutations and further determine possible correlations with clinicopathological parameters in Taiwanese patients with acral, non-chronic sun damaged (NCSD), or mucosal melanoma. MATERIALS & METHODS:Forty melanocytic nevi, 24 dysplastic nevi, and 175 melanomas from Taiwanese patients were analysed for mutations in BRAF, NRAS, MEK1, PI3K, and PTEN genes by PCR and direct sequencing. Immunohistochemical analysis of the respective proteins in nevi and melanomas were also performed to determine possible clinicopathological characteristics. RESULTS:In addition to the classic BRAF mutation, a novel BRAF mutation was identified in acral and sinonasal melanomas. A significantly reduced frequency of NRAS and BRAF mutations was noted compared with Caucasian-based studies. Increased immunohistochemical scores for pan-RAS and MEK1 and less nodal metastasis were associated with enhanced survival rates in acral and NCSD melanoma patients. CONCLUSIONS:Our findings suggest that oncogenic events may differ among melanomas in Asian patients geographically (e.g. between Japanese and Taiwanese patients). Moreover, distinct genetic alterations were noted among acral, NCSD, and mucosal melanoma patients in our study, and the expression of biomarkers correlated with clinical survival rates differentially among the various melanoma groups.
Analysis of Mucosal Melanoma Whole-Genome Landscapes Reveals Clinically Relevant Genomic Aberrations.
Zhou Rong,Shi Chaoji,Tao Wenjie,Li Jiang,Wu Jing,Han Yong,Yang Guizhu,Gu Ziyue,Xu Shengming,Wang Yujue,Wang Lizhen,Wang Yanan,Zhou Guoyu,Zhang Chenping,Zhang Zhiyuan,Sun Shuyang
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:Unlike advances in the genomics-driven precision treatment of cutaneous melanomas, the current poor understanding of the molecular basis of mucosal melanomas (MM) has hindered such progress for MM patients. Thus, we sought to characterize the genomic landscape of MM to identify genomic alterations with prognostic and/or therapeutic implications. EXPERIMENTAL DESIGN:Whole-genome sequencing (WGS) was performed on 65 MM samples, including 63 paired tumor blood samples and 2 matched lymph node metastases, with a further droplet digital PCR-based validation study of an independent MM cohort ( = 80). Guided by these molecular insights, the FDA-approved CDK4/6 inhibitor palbociclib was tested in an MM patient-derived xenograft (PDX) trial. RESULTS:Besides the identification of well-recognized driver mutations of (3.1%), family (6.2%), (7.8%), and (23.1%) in MMs, our study also found that (i) mutations and amplifications in the transmembrane nucleoporin gene (30.8%) defined a patient subgroup with higher tumor proliferation rates; (ii) enrichment of structural variations between chromosomes 5 and 12 defined a patient subgroup with significantly worse clinical outcomes; (iii) over 50% of the MM patients harbored recurrent focal amplification of several oncogenes ( and ) at 12q13-15, and this co-occurred significantly with amplification of at 5p15, which was verified in the validation cohort; (iv) the PDX trial demonstrated robust antitumor effects of palbociclib in MMs harboring amplification. CONCLUSIONS:Our largest-to-date cohort WGS analysis of MMs defines the genomic landscape of this deadly cancer at unprecedented resolution and identifies genomic aberrations that could facilitate the delivery of precision cancer treatments..
Oral melanoma and other pigmentations: when to biopsy?
Lambertini M,Patrizi A,Fanti P A,Melotti B,Caliceti U,Magnoni C,Misciali C,Baraldi C,Ravaioli G M,Dika E
Journal of the European Academy of Dermatology and Venereology : JEADV
Oral pigmentations (OPs) are often neglected, although a meticulous examination of the oral cavity is important not only in the diagnosis of oral melanoma, but also for the detection of important clinical findings that may indicate the presence of a systemic disease. OPs may be classified into two major groups on the basis of their clinical appearance: focal and diffuse pigmentations, even though this distinction may not appear so limpid in some cases. The former include amalgam tattoo, melanocytic nevi, melanoacanthoma and melanosis, while the latter include physiological/racial pigmentations, smoker's melanosis, drug-induced hyperpigmentations, postinflammatory hyperpigmentations and OPs associated with systemic diseases. We will discuss the most frequent OPs and the differential diagnosis with oral mucosal melanoma (OMM), underlining the most frequent lesions that need to undergo a bioptic examination and lesions that could be proposed for a sequential follow-up.
PTEN Methylation Dependent Sinonasal Mucosal Melanoma.
Lee Sang Hee,Roh Mi Ryung,Kang Beodeul,Park Kyu Hyun,Kim Soo Hee,Lee Sang Eun,Rha Sun Young
Cancer research and treatment : official journal of Korean Cancer Association
Sinonasal mucosal melanoma (SMM) is an aggressive and rare type of melanoma. Although the classic RAS-RAF-MEK pathway is thought to be the main pathway involved in melanoma pathogenesis, genetic alterations in the phosphatidylinositol 3-kinase-AKT pathway, including PTEN-regulated signaling, are also thought to contribute. So far, data regarding altered PTEN expression and epigenetic mechanism of PTEN silencing in development of SMM is extremely limited. Herein we report on a case of SMM with liver and bone metastases with an epigenetic alteration of PTEN. Results of mutation analysis for BRAF, NRAS, HRAS, KRAS, PIK3CA, c-Kit, and PTEN were negative; however, methylation of PTEN CpG islands was observed. Our case not only supports PTEN as a major tumor suppressor involved in melanoma tumorigenesis, but also a potential epigenetic mechanism of PTEN silencing in development of SMM.
Atypical and Mutations in Mucosal Melanoma.
Dumaz Nicolas,Jouenne Fanélie,Delyon Julie,Mourah Samia,Bensussan Armand,Lebbé Céleste
Primary mucosal melanomas represent a minority of melanomas, but have a significantly worse prognosis than cutaneous melanomas. A better characterization of the molecular pathogenesis of this melanoma subtype could help us understand the risk factors associated with the development of mucosal melanomas and highlight therapeutic targets. Because the Mitogen-Activated Protein Kinase (MAPK) pathway plays such a significant role in melanoma development, we explore v-raf murine sarcoma viral oncogene homolog B ( and neuroblastoma RAS viral oncogene homolog ( mutations in mucosal melanoma and compare them to the mutation profiles in cutaneous melanoma and other tumors with and mutations. We show that in addition to being less frequent, and mutations are different in mucosal melanoma compared to cutaneous melanomas. Strikingly, the and mutation profiles in mucosal melanoma are closer to those found in cancers such as lung cancer, suggesting that mutations in mucosal melanoma could be linked to some genotoxic agents that remain to be identified. We also show that the atypical and mutations found in mucosal melanomas have particular effects on protein activities, which could be essential for the transformation of mucosal melanocytes.
The mutational landscape of mucosal melanoma.
Nassar Kelsey W,Tan Aik Choon
Seminars in cancer biology
Mucosal melanoma is a rare and aggressive subtype of melanoma that has a less favorable prognosis due to the lack of understanding and identification of oncogenic drivers. Recently, whole genome and whole exome sequencing have unveiled the molecular landscape and potential oncogenic drivers of mucosal melanoma, which remains distinct from cutaneous melanoma. In this review, we provide an overview of the genomic landscape of mucosal melanoma, with a focus on molecular studies identifying potential oncogenic drivers allowing for a better mechanistic understanding of the biology of mucosal melanoma. We summarized the published genomics and clinical data supporting the observations that mucosal melanoma harbors distinct genetic alterations and oncogenic drivers from cutaneous melanoma, and thus should be treated accordingly. The common drivers (BRAF and NRAS) found in cutaneous melanoma have lower mutation rate in mucosal melanoma. In contrast, SF3B1 and KIT have higher mutation rate in mucosal melanoma as compared to cutaneous melanoma. From the meta-analysis, we also observed that the mutational profiles are slightly different between the "upper" and "lower" regions of mucosal melanoma, providing new insights and therapeutic options for the mucosal melanoma patients. Mutations identified in mucosal melanoma should be incorporated into routine clinical testing, as there are targeted therapies already developed for treating patients with these mutations in the precision medicine era.
The existence of early stage oral mucosal melanoma: A 10-year retrospective analysis of 170 patients in a single institute.
Wu Yunteng,Wang Lizheng,Ma Xuhui,Guo Wei,Ren Guoxin
BACKGROUND:Oral mucosal melanoma (OMM) is an aggressive tumor with an extremely low incidence, and the current TNM Staging System has classified all OMMs as high stage. However, controversy remains regarding the existence of early stage OMMs. PATIENTS AND METHODS:The clinical and pathological features, treatments and outcomes of 170 OMM patients treated in a single institution from January 2007 to July 2017 were retrospectively analyzed. Multivariate analysis was performed to identify significant prognostic factors for overall survival (OS). RESULTS:Multivariate analysis identified positive cervical lymph nodes (p < 0.0001), nodular OMMs (p < 0.0001), ulceration (p = 0.002), and level III or level IV invasion (p < 0.0001) as independent poor prognostic factors for OS. Nodular OMM patients with a tumor size ≤1 cm had a better outcome than those with a tumor size >1 cm (p < 0.0001). Twenty-two patients with superficial invasion had a favorable survival without the need of adjuvant therapy (postoperative chemotherapy or radiotherapy), and the current TNM Staging System was not suitable for those patients. Patients with deep invasion were more likely to suffer from recurrence and distant metastasis. CONCLUSIONS:Tumor size ≤1 cm and OMM in situ, although extremely rare, do exist. It is advisable for AJCC to consider tumor size ≤1 cm and OMM in situ as the early stage of OMM when updating the new Oral Melanoma Staging System.
Mucosal melanomas: Site-specific information, comparisons with cutaneous tumors, and differential diagnosis.
Dominiak Nicole R,Wick Mark R,Smith M Timothy
Seminars in diagnostic pathology
Melanoma of the skin is the fifth leading new cancer diagnosis, having accounted for almost 77,000 cases and more than 9000 deaths in the United States in 2013. Although cutaneous neoplasms of this type are relatively common, their mucosal counterparts are not. Mucosal melanomas comprise approximately 1.3% of all melanocytic malignancies. Although they are rare, these lesions present at an advanced stage with more adverse prognoses. In addition, at a molecular level, they have proven to be distinct entities because they possess genetic mutations not usually seen in their cutaneous counterparts. Conversely, a sizable proportion of mucosal melanomas lack the gene aberrations seen in cutaneous melanomas. Such findings indicate different pathways in tumorigenesis for the two subtypes. Because melanomas arising from the mucosae are not often encountered, very little has been published on staging guidelines and prognostic factors. This causes dilemmas for both patients and physicians. Further work is necessary to define staging systems for all mucosal locations, so that accurate prognoses can be assigned to such lesions.
Medical bioinformatics in melanoma.
Cheng Phil F
Current opinion in oncology
PURPOSE OF REVIEW:Bioinformatic insights from next-generation sequencing has been integral in understanding melanoma biology, resistance to treatment and provided new avenues for melanoma treatment. Whole-genome sequencing, whole-exome sequencing and RNA sequencing has redefined the molecular classification of melanoma, revealed distinct genetic aberrations that define clinical subtypes of melanoma and uncovered the diverse heterogeneity that resides in an individual tumor. RECENT FINDINGS:In this review, we will summarize the recent whole-genome study that catalogs the genomic landscape across many melanoma subtypes, the single-cell RNA sequencing studies that interrogates tumor heterogeneity and the personalized vaccine approaches to melanoma treatment. SUMMARY:Whole-genome sequencing of diverse subtypes of melanoma revealed acral and mucosal subtypes to have a different genomic landscape compared with cutaneous melanoma. Acral and mucosal melanomas are characterized by low mutation burden and high structural variants. Single-cell RNA sequencing revealed high intratumoral heterogeneity and the existence of rare intrinsic drug-resistant populations. Lastly, vaccination against tumor neoantigens could be a potential personalized medicine therapy for melanoma patients. In summary, bioinformatics research is deeply ingrained in all aspects of melanoma research and will continue to blossom together for many years to come.
Oncogenic BRAF fusions in mucosal melanomas activate the MAPK pathway and are sensitive to MEK/PI3K inhibition or MEK/CDK4/6 inhibition.
Kim H S,Jung M,Kang H N,Kim H,Park C-W,Kim S-M,Shin S J,Kim S H,Kim S G,Kim E K,Yun M R,Zheng Z,Chung K Y,Greenbowe J,Ali S M,Kim T-M,Cho B C
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated. We biologically characterized a novel ZNF767-BRAF fusion found in a vemurafenib-refractory respiratory tract PMM, from which cell line harboring ZNF767-BRAF fusion were established for further molecular analyses. In an independent data set, NFIC-BRAF fusion was identified in an oral PMM case and TMEM178B-BRAF fusion and DGKI-BRAF fusion were identified in two malignant melanomas with a low mutational burden (number of mutation per megabase, 0.8 and 4, respectively). Subsequent analyses revealed that the ZNF767-BRAF fusion protein promotes RAF dimerization and activation of the MAPK pathway. We next tested the in vitro and in vivo efficacy of vemurafenib, trametinib, BKM120 or LEE011 alone and in combination. Trametinib effectively inhibited tumor cell growth in vitro, but the combination of trametinib and BKM120 or LEE011 yielded more than additive anti-tumor effects both in vitro and in vivo in a melanoma cells harboring the BRAF fusion. In conclusion, BRAF fusions define a new molecular subset of PMM that can be targeted therapeutically by the combination of a MEK inhibitor with PI3K or cyclin-dependent kinase 4/6 inhibitors.
Mucosal melanomas in the racially diverse population of California.
Altieri Lisa,Wong Michael K,Peng David H,Cockburn Myles
Journal of the American Academy of Dermatology
BACKGROUND:Mucosal melanomas are rare, poorly understood neoplasms without a consensus standard of care. OBJECTIVE:We sought to define mucosal melanoma tumor characteristics and the racial/ethnic attributes of patients with mucosal melanomas. METHODS:We analyzed 130,920 cutaneous melanomas and 1919 mucosal melanomas recorded in the population-based California Cancer Registry from 1988 to 2013. RESULTS:Although only 1% of melanomas occurring in nonHispanic whites were mucosal, other racial/ethnic groups had a higher proportion of mucosal melanomas (15% for Asian/Pacific Islanders, 9% for nonHispanic blacks, and 4% for Hispanics). Anorectal mucosal melanomas were most common in female Asian/Pacific Islanders, whereas genitourinary mucosal melanomas were highest in nonHispanic whites, and head and neck tumors were most common among Hispanics. Stage at presentation was not uniform among racial/ethnic groups, with Asian/Pacific Islanders having the highest rates of metastasis. LIMITATIONS:The lack of a standardized staging system for mucosal melanomas confounds classification and knowledge regarding metastasis. Small sample size limits comparative analysis across race, stage, site, and depth. CONCLUSION:Mucosal melanomas differ by race/ethnicity with regard to anatomic site, stage, and depth. Because early detection offers the best chance of increased survival, greater awareness will aid clinicians who care for patients at risk for these aggressive tumors.
GNAQ and GNA11 mutations occur in 9.5% of mucosal melanoma and are associated with poor prognosis.
Sheng Xinan,Kong Yan,Li Yiqian,Zhang Qiannan,Si Lu,Cui Chuanliang,Chi Zhihong,Tang Bixia,Mao Lili,Lian Bin,Wang Xuan,Yan Xieqiao,Li Siming,Dai Jie,Guo Jun
European journal of cancer (Oxford, England : 1990)
BACKGROUND:Mucosal melanoma (MM) is a rare subtype of melanoma in Caucasians with extremely poor prognosis, and therapy strategy has not been clearly established for MM. We aimed to investigate the genetic aberrations possibly applicable in targeted therapy of MM. We examined the somatic mutations of GNAQ and GNA11 (GNAQ/11, encoding the guanine nucleotide-binding alpha subunits) in MM and evaluated their correlation to clinicopathologic features of MM. METHODS:This study collected samples from primary lesions of 284 MM patients. Tissue samples were analysed for mutations in exons 4 and 5 of GNAQ/11 in genomic DNA by polymerase chain reaction amplification and Sanger sequencing. Correlations of GNAQ/11 mutations to clinicopathologic features and prognosis of MM were evaluated. RESULTS:The overall mutation frequency of GNAQ/11 in MM was 9.5% (27 in 284), with a frequency of 4.6% and 4.9% for GNAQ and GNA11 mutations, respectively. The mutations in exon 5 of GNAQ/11 occurred exclusively in codon 209. GNAQ(Q209L) was the most prevalent variation (92.3% of missense GNAQ mutations). GNAQ/11 mutations were not significantly associated with age, gender, ulceration, and primary anatomic site. The median overall survival for MM patients with GNAQ mutations (16.0 versus 26.0 months, P = 0.031) or GNA11 mutations (15.0 versus 26.0 months, P = 0.039) were significantly shorter than those for patients with wild-type GNAQ and GNA11, respectively. CONCLUSIONS:Our study suggests that GNAQ and GNA11 mutations occur frequently in MM and may be a prognostic factor for MM. Our data implicate that GNAQ/11 may be potential targets for targeted therapy of MM.
Predominance of triple wild-type and IGF2R mutations in mucosal melanomas.
Iida Yuuki,Salomon Matthew P,Hata Keisuke,Tran Kevin,Ohe Shuichi,Griffiths Chester F,Hsu Sandy C,Nelson Nellie,Hoon Dave S B
BACKGROUND:Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment. METHODS:Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry. RESULTS:Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002). CONCLUSIONS:These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.
Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.
Grözinger Gerd,Mann Steven,Mehra Tarun,Klumpp Bernhard,Grosse Ulrich,Nikolaou Konstantin,Garbe Claus,Clasen Stephan
OBJECTIVES:Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. METHODS:A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. RESULTS:Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. CONCLUSIONS:Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. KEY POINTS:• Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.
Risk-based stratification in head and neck mucosal melanoma.
Moya-Plana Antoine,Mangin David,Dercle Laurent,Taouachi Rabah,Casiraghi Odile,Ammari Samy,Nguyen France,Temam Stéphane,Robert Caroline,Gorphe Philippe
BACKGROUND:Head and neck mucosal melanoma (HNMM) is a rare and aggressive disease with a high metastatic potential. Two staging systems are currently available: one specific to HNMM (mmTNM) and one specific to primary tumour sites (sccTNM). Our main objective was to assess the prognostic value of both of these classifications in order to allow accurate risk-based classification. METHODS:We performed a retrospective cohort study of patients with HNMM treated consecutively between 2000 and 2017. All of the patients were restaged using the mmTNM and the sccTNM. A prognostic analysis was carried out according to both staging systems. RESULTS:There were 96 patients with an HNMM in our cohort, of whom 80 underwent surgical treatment followed by radiotherapy. The median overall survival (OS) and progression-free survival (PFS) for the operated patients were 39 months (95% CI, 21.6-56.4 months) and 18 months (95% CI, 6.5-29.5 months), respectively. A paranasal sinus localization was associated with lower survival compared to a nasal cavity primary localization (p < 1 0). Both of the classifications correlated with OS, PFS, and distant metastasis-free survival. High-risk HNMM were characterized as T4/stage IV by the mmTNM and T3-4/stage III-IV by the sccTNM. Given the primary tumour location, both TNM classifications were suitable for risk-stratification of sinonasal mucosal melanomas. However, combining both TNM, we defined new stages mmT3A and mmT3B according to sccTNM with a more accurate risk stratification (p < 1 0). CONCLUSIONS:Both of the classifications should be combined, in order to improve the risk-stratification of patients with HNMM.
Mucosal melanoma: clinical, histological and c-kit gene mutational profile of 86 French cases.
Cinotti E,Chevallier J,Labeille B,Cambazard F,Thomas L,Balme B,Leccia M T,D'Incan M,Vercherin P,Douchet C,Rubegni P,Perrot J L
Journal of the European Academy of Dermatology and Venereology : JEADV
BACKGROUND:Mucosal melanomas are rare and highly aggressive tumours. Few studies evaluated mucosal melanomas of locations other than the head and neck region, and other than those of the Asian population. OBJECTIVES:The objective of this study was to analyse the clinical and histological features, as well as the mutational status of c-kit and b-raf gene of mucosal melanoma in any localization in a French series. METHODS:We investigated clinical (sex, age, performance status, survival, treatment of the patients and lack of pigmentation of the tumours) and histopathological features (ulceration, Breslow's index, mitotic rate), as well as the mutational status of c-kit and b-raf of 86 mucosal melanomas diagnosed in 15 years in four French University Hospitals. RESULTS:Most melanomas affected women (72%) and the genital region (46.5%). A fifth of melanomas were amelanotic. 81% of melanomas had a Breslow's index ≥1, whereas all glans melanomas, and most vulvar melanomas had a Breslow index ≤1 mm. Overall survival was 54% at 3 years; 11.6% of the 43 tested mucosal melanomas were c-kit-mutated while the 15 tested genital melanomas were not. The c-kit gene mutation did not influence the overall survival. Age ≥ 50, amelanotic type and performance status ≥1 were not poor prognostic factors in our series. CONCLUSION:This study confirmed that mucosal melanomas are rare and could be difficult to diagnose being often amelanotic and in hidden sites. Most melanomas were thick at the diagnosis, but glans and vulvar melanomas were thinner probably because of their greater visibility. The frequency of the c-kit mutation varied depending on the initial tumour site. In our series, the prognosis was poor, independently from c-kit mutations and the patient's general health and age. The presence of metastasis at diagnosis was associated with a worse prognosis indicating the importance of an early diagnosis.
Human tumor genomics and zebrafish modeling identify loss as a driver of mucosal melanoma.
Ablain Julien,Xu Mengshu,Rothschild Harriet,Jordan Richard C,Mito Jeffrey K,Daniels Brianne H,Bell Caitlin F,Joseph Nancy M,Wu Hong,Bastian Boris C,Zon Leonard I,Yeh Iwei
Science (New York, N.Y.)
Melanomas originating from mucosal surfaces have low mutation burden, genomic instability, and poor prognosis. To identify potential driver genes, we sequenced hundreds of cancer-related genes in 43 human mucosal melanomas, cataloging point mutations, amplifications, and deletions. The gene, which encodes a negative regulator of mitogen-activated protein kinase (MAPK) signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, we found that functions as a tumor suppressor, particularly in the context of mutations. knockdown caused MAPK activation, increased cell proliferation, and conferred resistance to drugs inhibiting KIT tyrosine kinase activity. These findings provide a rationale for MAPK inhibition in SPRED1-deficient melanomas and introduce a zebrafish modeling approach that can be used more generally to dissect genetic interactions in cancer.
Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma.
Hou June Y,Baptiste Caitlin,Hombalegowda Radhika Bangalore,Tergas Ana I,Feldman Rebecca,Jones Nathaniel L,Chatterjee-Paer Sudeshna,Bus-Kwolfski Ama,Wright Jason D,Burke William M
BACKGROUND:Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers. METHODS:In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel. RESULTS:In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B-Raf proto-oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF-mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD-L1 (56%) and PD-1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had KIT mutations, wild-type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A). CONCLUSIONS:The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333-1344. © 2016 American Cancer Society.
Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma.
Wong Kim,van der Weyden Louise,Schott Courtney R,Foote Alastair,Constantino-Casas Fernando,Smith Sionagh,Dobson Jane M,Murchison Elizabeth P,Wu Hong,Yeh Iwei,Fullen Douglas R,Joseph Nancy,Bastian Boris C,Patel Rajiv M,Martincorena Inigo,Robles-Espinoza Carla Daniela,Iyer Vivek,Kuijjer Marieke L,Arends Mark J,Brenn Thomas,Harms Paul W,Wood Geoffrey A,Adams David J
Mucosal melanoma is a rare and poorly characterized subtype of human melanoma. Here we perform a cross-species analysis by sequencing tumor-germline pairs from 46 primary human muscosal, 65 primary canine oral and 28 primary equine melanoma cases from mucosal sites. Analysis of these data reveals recurrently mutated driver genes shared between species such as NRAS, FAT4, PTPRJ, TP53 and PTEN, and pathogenic germline alleles of BRCA1, BRCA2 and TP53. We identify a UV mutation signature in a small number of samples, including human cases from the lip and nasal mucosa. A cross-species comparative analysis of recurrent copy number alterations identifies several candidate drivers including MDM2, B2M, KNSTRN and BUB1B. Comparison of somatic mutations in recurrences and metastases to those in the primary tumor suggests pervasive intra-tumor heterogeneity. Collectively, these studies suggest a convergence of some genetic changes in mucosal melanomas between species but also distinctly different paths to tumorigenesis.
The natural history and patterns of metastases from mucosal melanoma: an analysis of 706 prospectively-followed patients.
Lian B,Cui C L,Zhou L,Song X,Zhang X S,Wu D,Si L,Chi Z H,Sheng X N,Mao L L,Wang X,Tang B X,Yan X Q,Kong Y,Dai J,Li S M,Bai X,Zheng N,Balch C M,Guo J
Annals of oncology : official journal of the European Society for Medical Oncology
Background:We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites. Patients and methods:Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites. Results:The anatomic sites of the primary mucosal melanomas were from the lower GI tract (26.5%), nasal cavity and paranasal sinuses (23%), gynecological sites (22.5%), oral cavity (15%), urological sites (5%), upper GI tract (5%), and other sites (3.0%). At initial diagnosis, 14.5% were stage I disease, 41% Stage II, 21.5% Stage III, and 23.0% stage IV. Predominant metastatic sites were regional lymph nodes (21.5%), lung (21%), liver (18.5%), and distant nodes (9%). Oral cavity mucosal melanoma had a higher incidence of regional nodal metastases (31.7% versus 19.8%, P = 0.009), and a higher incidence of lung metastases (32.5% versus 18.5%, P = 0.007) compared to other primary mucosal melanomas. There was a 10% incidence of CKIT mutation and 12% BRAF mutation. Mucosal melanomas from nasal pharyngeal and oral, gastrointestinal, gynecological, and urological had a similar survival with a 1-year survival rate (88%, 83%, 86%), 2-year survival rate (66%, 57%, 61%), 5-year survival rate (27%, 16%, 20%), respectively. Conclusions:The largest sample size allows, for the first time, a comparison of primary melanoma stage and patterns of metastases across anatomical sites. With few exceptions, the presenting stages, incidence of nodal and distant metastases, the site of predilection of distant metastases, or overall survival were similar despite different primary anatomic sites. These findings suggest that clinical trials involving mucosal melanomas and the administration of systemic therapy can be applied equally to mucosal melanomas regardless of their primary anatomic site.