Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi

Yeh, Iwei; Lang, Ursula E.; Durieux, Emeline; Tee, Meng Kian; Jorapur, Aparna; Shain, A. Hunter; Haddad, Véronique; Pissaloux, Daniel; Chen, Xu; Cerroni, Lorenzo; Judson, Robert L.; LeBoit, Philip E.; McCalmont, Timothy H.; Bastian, Boris C.; Fouchardière, Arnaud de la

doi:10.1038/s41467-017-00758-3

Cited by 110 publications

(149 citation statements)

References 46 publications

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“…Just as combined BAP1 and BRAF V600E mutations are characteristic of cutaneous BIMT, concurrent BAP1/SF3B1 and GNAQ/GNA11 mutations correspond with blue‐nevus‐like melanoma . Similarly, simultaneous β‐catenin ( APC/CTNNB1 ) and MAPK pathway mutations correspond with deep penetrating nevus, and spitzoid melanocytic tumors may bear ALK, NTRK , and ROS fusions . These findings together support an approach to mutational analysis that is multifactorial and considers the progressive acquisition of molecular genetic alterations that themselves correlate with distinctive morphologic change.…”

Section: Introductionmentioning

confidence: 99%

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

2019

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Although discussed using variable terminology, cutaneous BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumor (BIMT) has been considered a discrete diagnostic entity since 2011. Here, we review the initial genomic studies that identified these distinct melanocytic tumors and the clinical and histopathological features that define these tumors. These epithelioid, predominantly dermal, and melanocytic tumors present as erythematous nodules and histopathologically have features that may overlap with Spitz nevi and nevoid melanoma. There is no sex predilection, and cutaneous BIMTs can appear at any age; however, in most familial (germline mutant) cases patients have multiple cutaneous tumors with a first diagnosis in the second or third decade of life; ocular melanoma and other tumors are increasingly identified in these kindreds with germline BAP1 mutation. These tumors have been described with a myriad of terms including: Wiesner nevus, nevoid melanoma‐like melanocytic proliferation (NEMMP), BAP1 mutant Spitz nevus, BAP1 mutant nevoid melanoma, cutaneous BAPoma, and most recently cutaneous BIMT.

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Section: Introductionmentioning

confidence: 99%

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

2019

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“…In fact, a recent study has provided genetic support for the latter hypothesis. Based on DNA‐sequencing of known oncogenes, a new study identified the presence of activating mutations of the β‐catenin pathway in 17 out of 18 deep penetrating nevi . Moreover, the authors proposed changes in mutated β‐catenin pathway could account for the increased pigmentation and increased cell volume, 2 histopathological features shared by deep penetrating nevi and inverted type‐A nevi.…”

Section: Discussionmentioning

confidence: 99%

Histological features and outcome of inverted type‐A melanocytic nevi

Dadras

Zembowicz

et al. 2018

J Cutan Pathol

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The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a pre-existing nevus, causing over-interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark's) level of IV-V, there was no ulceration, significant regression or inflammation. Up to 2 mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that "inverted type-A nevus" might be considered a variant of the two.

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“…In addition, potential errors in reporting of nevus-associated melanomas could derive as a result of collision events of a melanoma with an adjacent nevus or the predominance of nevus remnants by the melanoma cells. (Yeh et al, 2017). Different genetic alterations have been also found in pigmented epithelioid melanocytomas (Cohen et al, 2017).…”

Section: Dn As Potential Melanoma Precursorsmentioning

confidence: 98%

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

Orfanidis

2020

Linköping University Medical Dissertations

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Melanoma is a form of cancer that develops in melanocytes. While it represents only 5% of skin malignancies, it is the most aggressive and lethal. Benign proliferation of these cells form the melanocytic nevi. The definitive diagnosis of melanocytic nevi or melanoma lesions is histopathologic. However, it is estimated that a correct diagnosis is established by means of standard skin biopsy in only 83% of the melanocytic lesions; of the remaining cases 8% and 9% are overinterpreted (false positives) and under-interpreted (false negatives), respectively. This underscores the importance of additional diagnostic tests. Since cellular senescence is considered to be a tumor suppressive mechanism, immuno-histochemistry using senescence markers has been suggested for the evaluation of difficult melanocytic lesions; however, the routinely used senescence markers lack the ability to distinguish nevi from melanoma. The general aim of this thesis is therefore to identify novel senescence markers that may aid in melanoma diagnosis.In study I, we established a cellular model with nevus-mimicking characteristics consisting in primary melanocytes that become senescent. Transcriptomic analysis allowed expanding the set of senescence-associated markers that could distinguish nevi from melanoma and identifying tubulin β-3 as a potential diagnostic marker. Depletion of tubulin β-3 and pretreatment with tubulin destabilizing drugs in melanocytes and melanoma cells induced a senescence-like phenotype in vitro. In particular, reduced migration capacity and induction of cell cycle arrest in G2/M phase of the cell cycle was demonstrated.In study II, a potential inter-cellular signaling pathway between melanoma cells and stromal fibroblasts, that might facilitate melanoma invasion, was investigated. Ultraviolet (UV) radiation was shown, both in melanoma cells and fibroblasts, to promote the release and activation of TGF-β1 and subsequent increase in expression of the serine protease FAP-α, a protein that plays role in extracellular matrix degradation and therefore facilitates the invasion of melanoma cells. Such mechanism was not functional in senescent melanocytes.In study III, it was shown that tubulin β-3 immunostaining aids in the diagnosis of nevi and melanomas. The diagnostic criterium was the tubulin β-3 gradient within the melanocytic nevi that was no longer apparent in melanoma. Different patterns of tubulin β-3 immunostaining in melanoma were described, dermoscopy-immunohistochemistry associations were found, specific dermoscopic features highlighted, and the prognostic value of this tubulin β-3 marker was examined. The progression rate in patients whose melanomas had areas with loss of tubulin β-3 was 4 times higher than in patients without this feature, although statistical significance could not be reached (p=0.06).In conclusion, transcriptomic analysis expanded the set of senescence-associated markers that could distinguish nevi from melanoma and identified tubulin β-3 as novel immunohistochemistry marker shown to have diagn...

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Combined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi

Cited by 110 publications

References 46 publications

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

BRCA1‐associated protein (BAP1)‐inactivated melanocytic tumors

Histological features and outcome of inverted type‐A melanocytic nevi

Identification and clinical evaluation of senescence-associated markers to distinguish melanocytic nevi from melanomas

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