The Molecular Pathology of Melanoma: An Integrated Taxonomy of Melanocytic Neoplasia

Bastian, Boris C.

doi:10.1146/annurev-pathol-012513-104658

Cited by 427 publications

(424 citation statements)

References 146 publications

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“…As our understanding of the molecular changes that accompany melanomagenesis increases [14,53], it has become apparent that in contrast to non-melanoma skin cancer, the singular role of UVR in melanomagenesis has become less certain [166,167]. Not all of the attributable risk for cutaneous melanoma can be linked to UVR exposure, and the molecular pathology suggests that UVR alone may not be the etiologic agent [14].…”

Section: Chromiummentioning

confidence: 99%

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Melanoma Epidemiology and Prevention

Berwick

Buller

Cust

et al. 2015

Cancer Treatment and Research

122

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The epidemiology of melanoma is complex, and individual risk depends on sun exposure, host factors, and genetic factors, and in their interactions as well. Sun exposure can be classified as intermittent, chronic, or cumulative (overall) exposure, and each appears to have a different effect on type of melanoma. Other environmental factors, such as chemical exposures-either through occupation, atmosphere, or food-may increase risk for melanoma, and this area warrants further study. Host factors that are well known to be important are the numbers and types of nevi and the skin phenotype. Genetic factors are classified as

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Section: Chromiummentioning

confidence: 99%

“…Not all of the attributable risk for cutaneous melanoma can be linked to UVR exposure, and the molecular pathology suggests that UVR alone may not be the etiologic agent [14]. Additionally, only about 10 % of melanomas have a strong Mendelian (heritable) component.…”

Section: Chromiummentioning

confidence: 99%

Melanoma Epidemiology and Prevention

Berwick

Buller

Cust

et al. 2015

Cancer Treatment and Research

122

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“…1,10,11 The incidence of acral melanoma, defined as those arising on glabrous skin of the palms and soles and in the nail apparatus, is similar across different populations. 12 Furthermore, acral melanomas are thought to be protected from UVR by a thick strata corneum 13 or nail plate. 14 Therefore, it has been hypothesized that acral and sun-shielded mucosal melanomas have different genetic causal pathways unrelated to UVR exposure.…”

mentioning

confidence: 99%

Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas

Rawson

Johansson

Hayward

et al. 2017

Laboratory Investigation

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Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Wholegenome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35 = 8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140 = 2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

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“…In the absence of UV-mediated events in mucosal and acral skin, a combination of (1) early chromosomal instability, characterized by copy number gains in TERT, CCND1, and KIT, and (2) non-UV-related activating mutations in KIT and PDGFRA lead to tumor proliferation (Table 1). Hence, it is the presence of early chromosomal copy number aberrations, with gains in select 65 The activation of TERT provides cells with a growth advantage and the ability to avoid telomere shorteninginduced senescence, which typically occurs after 100 0 00 rounds of replication. We postulate that the later onset of acral and mucosal melanomas suggests that increased TERT activity may be present at a very early stage or present in more slowly dividing, and possibly non-tumoral, cells.…”

Section: Inherited and Other Risk Factorsmentioning

confidence: 99%

Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features

Merkel

Gerami

2017

Laboratory Investigation

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In most cases of cutaneous melanoma, ultraviolet (UV) radiation is recognized as a prominent risk factor. Less is known regarding the mechanisms of mutagenesis for melanoma arising in sun-protected sites, such as acral and mucosal melanoma. Acral and mucosal melanoma share many common features, including a late age of onset, a broad radial growth phase with prominent lentiginous growth, the presence of field cancerization cells, and, in most cases, lack of a precursor nevus. In addition to early chromosomal instability, many of the same genes are also involved in these two distinct melanoma subtypes. To better understand non-UV-mediated pathogenesis in melanoma, we conducted a joint literature review of clinical, histological, and molecular features in acral and mucosal melanoma. We also reviewed the current literature regarding aberrations in KIT, PDGFRA, TERT, and other commonly involved genes. By comparing common features of these two subtypes, we suggest potential mechanisms underlying acral and/or mucosal melanoma and offer direction for future investigations.

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The Molecular Pathology of Melanoma: An Integrated Taxonomy of Melanocytic Neoplasia

Cited by 427 publications

References 146 publications

Melanoma Epidemiology and Prevention

Melanoma Epidemiology and Prevention

Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas

Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features

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