Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations

Houlier, Aurélie; Pissaloux, Daniel; Masse, Ingrid; Tirode, Franck; Karanian, Marie; Pincus, Laura B.; McCalmont, Timothy H.; LeBoit, Philip E.; Bastian, Boris C.; Yeh, Iwei; Fouchardière, Arnaud de la

doi:10.1038/s41379-019-0384-8

Cited by 48 publications

(61 citation statements)

References 36 publications

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“…In comparison, Spitz nevi represented only a small portion (8%) of cases in this Spitz subgroup (23,53,91,92,98). Houlier et al reported the largest series of 33 cases of Spitz melanocytic proliferations with MAP3K8 fusions, of which 13 (40%) were classified as atypical Spitz tumors and 15 (45%) as Spitz melanomas (92). Moreover, 77% of these atypical Spitz tumors and Spitz melanomas harbored CDKN2A (92) inactivation, which was also reported as one of the most common secondary genetic events in some other series (23,83,91).…”

Section: Map3k8 Fusionsmentioning

confidence: 91%

“…A literature review revealed that most Spitz proliferations with MAP3K8 fusion or truncations, a MAP3K3 fusion, and a MAP2K1 p.I103_K104del were classified either as atypical Spitz tumors or Spitz melanomas (40% and 52%, respectively). In comparison, Spitz nevi represented only a small portion (8%) of cases in this Spitz subgroup (23,53,91,92,98). Houlier et al reported the largest series of 33 cases of Spitz melanocytic proliferations with MAP3K8 fusions, of which 13 (40%) were classified as atypical Spitz tumors and 15 (45%) as Spitz melanomas (92).…”

Section: Map3k8 Fusionsmentioning

confidence: 99%

“…A number of different MAP3K8 fusion partners have been identified, including SVIL (9,23,92,93), DIP2C (53,83,91,92) MAP3K8 fusions and truncations have also been identified in ovarian, lung, and breast carcinomas, mesotheliomas, cutaneous myxoinflammatory fibroblastic sarcoma, squamous cell carcinomas, and melanocytic tumors -in rare acral melanomas and Spitz neoplasms (9,23,53,83,(92)(93)(94)(95)(96)(97).…”

Section: Map3k8 Fusionsmentioning

confidence: 99%

“…Additional characteristic features include focal hyperpigmented dermal clones and giant multinucleated melanocytes. Deep mitotic activity is not uncommon (9,23,53,91,92). Furthermore, desmoplastic stromal reaction and focal pagetoid scatter can be seen in 73% and 45% of cases, respectively (92).…”

Section: Map3k8 Fusionsmentioning

confidence: 99%

“…The biological behavior of Spitz melanocytic proliferations with a MAP3K8 fusion is variable; it appears that the prognosis depends on the presence of these additional genetic aberrations. Biallelic inactivation of CDKN2A, demonstrated either by p16 immunohistochemistry (with focal or diffuse complete loss of p16 expression) or molecular ge- (23,83,91,92), followed by TERT promotor mutations and a complex TERT structural rearrangement, albeit less frequently (9,83).…”

Section: Map3k8 Fusionsmentioning

confidence: 99%

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An Update on Molecular Genetic Aberrations in Spitz Melanocytic Proliferations: Correlation with Morphological Features and Biological Behavior

Šekoranja

Pižem

Luzar

2021

ama

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The aim of the paper is to give an update on molecular genetic aberrations in Spitz melanocytic proliferations with special em- phasis on their correlation with morphological features and biological behavior. The Spitz group of melanocytic proliferations is defined by a combination of distinctive morphological features and driver molecular genetic events. Morphologically, these neoplasms are characterized by large, oval, polygonal, or spindled melanocytes with abundant eosinophilic cytoplasm, vesicular nuclei with prominent nucleoli, often in association with epidermal hyperplasia. Molecular aberrations in Spitz melanocytic proliferations can be divided into two main groups, according to the driver genetic change: 1) 11p amplification/HRAS muta- tion, present in about 20% of cases, and 2) kinase fusions, present in about 50%, further subdivided into tyrosine kinase fusions (ALK, ROS1, NTRK1, NTRK3, MET, RET) or serine-threonine kinase fusions (MAP3K8, BRAF). Driver genetic aberrations can be detected along the whole biological spectrum of Spitz melanocytic proliferations, and are mutually exclusive. Although driver genetic aberrations enable proliferation of melanocytes, additional genetic events (often biallelic inactivation of CDKN2A and TERT promoter mutations) are necessary for the development of overt Spitz malignancy.Conclusions. Recent studies have demonstrated that certain driver genetic aberrations are more often associated with the benign spectrum of Spitz melanocytic proliferations and indolent biological behavior (11p amplification/HRAS mutation, tyrosine kinase fusions). In contrast, some driver aberrations are more frequent in the atypical/malignant spectrum of Spitz melanocytic proliferations with a potential for aggressive biological behavior (serine-threonine kinase fusions). In addition, certain driver aberrations are often associated with distinctive morphological features. However, none of the morphological features is entirely specific for any of these driver genetic aberrations. Immunohistochemistry for ALK, ROS1, and pan-TRK can be used for screening purposes to detect cor- responding fusion proteins.

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Section: Map3k8 Fusionsmentioning

confidence: 91%

Section: Map3k8 Fusionsmentioning

confidence: 99%

Section: Map3k8 Fusionsmentioning

confidence: 99%

Section: Map3k8 Fusionsmentioning

confidence: 99%

Section: Map3k8 Fusionsmentioning

confidence: 99%

See 3 more Smart Citations

An Update on Molecular Genetic Aberrations in Spitz Melanocytic Proliferations: Correlation with Morphological Features and Biological Behavior

Šekoranja

Pižem

Luzar

2021

ama

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Wholistic approach: Transcriptomic analysis and beyond using archival material for molecular diagnosis

Macagno

Pissaloux

Fouchardière

et al. 2022

Genes Chromosomes & Cancer

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Many neoplasms remain unclassified after histopathological examination, which requires further molecular analysis. To this regard, mesenchymal neoplasms are particularly challenging due to the combination of their rarity and the large number of subtypes, and many entities still lack robust diagnostic hallmarks. RNA transcriptomic profiles have proven to be a reliable basis for the classification of previously unclassified tumors and notably for mesenchymal neoplasms. Using exome-based RNA capture sequencing on more than 5000 samples of archival material (formalin-fixed, paraffin-embedded), the combination of expression profiles analyzes (including several clustering methods), fusion genes, and small nucleotide variations has been developed at the Centre Léon Bérard (CLB) in Lyon for the molecular diagnosis of challenging neoplasms and the discovery of new entities. The molecular basis of the technique, the protocol, and the bioinformatics algorithms used are described herein, as well as its advantages and limitations.

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Genetic and methylation profiles distinguish benign, malignant and spitzoid melanocytic tumors

Zaremba

Jansen

Murali

et al. 2022

Intl Journal of Cancer

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Accurate classification of melanocytic tumors is important for prognostic evaluation, treatment and follow-up protocols of patients. The majority of melanocytic proliferations can be classified solely based on clinical and pathological criteria, however in select cases a definitive diagnostic assessment remains challenging and additional diagnostic biomarkers would be advantageous. We analyzed melanomas, nevi, Spitz nevi and atypical spitzoid tumors using parallel sequencing (exons of 611 genes and 507 gene translocation analysis) and methylation arrays (850k Illumina EPIC). By combining detailed genetic and epigenetic analysis with reference-based and reference-free DNA methylome deconvolution we compared Spitz nevi to nevi and melanoma and assessed the potential for these methods in classifying challenging spitzoid tumors. Results were correlated with clinical and histologic features. Spitz nevi were found to cluster independently of nevi and melanoma and demonstrated a different mutation profile. Multiple copy number alterations and TERT promoter mutations were identified only in melanomas. Genomewide methylation in Spitz nevi was comparable to benign nevi while the Leukocytes UnMethylation for Purity (LUMP) algorithm in Spitz nevi was comparable to melanoma.Histologically difficult to classify Spitz tumor cases were assessed which, based on methylation arrays, clustered between Spitz nevi and melanoma and in terms of genetic profile or copy number variations demonstrated worrisome features suggesting a malignant neoplasm. Comprehensive sequencing and methylation analysis verify Spitz nevi as an

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Melanocytic tumors with MAP3K8 fusions: report of 33 cases with morphological-genetic correlations

Cited by 48 publications

References 36 publications

An Update on Molecular Genetic Aberrations in Spitz Melanocytic Proliferations: Correlation with Morphological Features and Biological Behavior

An Update on Molecular Genetic Aberrations in Spitz Melanocytic Proliferations: Correlation with Morphological Features and Biological Behavior

Wholistic approach: Transcriptomic analysis and beyond using archival material for molecular diagnosis

Genetic and methylation profiles distinguish benign, malignant and spitzoid melanocytic tumors

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