Activating MET kinase rearrangements in melanoma and Spitz tumours

Yeh, Iwei; Botton, Thomas; Talevich, Eric; Shain, A. Hunter; Sparatta, Alyssa J.; Fouchardière, Arnaud de la; Mully, Thaddeus W.; North, Jeffrey P.; Garrido, María C.; Gagnon, Alexander; Vemula, Swapna; McCalmont, Timothy H.; LeBoit, Philip E.; Bastian, Boris C.

doi:10.1038/ncomms8174

Cited by 140 publications

(127 citation statements)

References 48 publications

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“…24 Genomic rearrangements (translocations, kinase fusions) of various receptor tyrosine kinases, including ALK , ROS1 , NTRK1 , RET , and MET , or the serine-threonine kinase BRAF are observed in up to 50% of Spitz tumours. 25,26 …”

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

“…25,26 Patients with fusion positive Spitz tumours are younger than patients whose tumours lack translocations, 25 a feature also shared by patients with kinase fusion-driven lung cancers, 54 thyroid cancers, 55 and astrocytomas. 56 …”

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

“…Genomic rearrangements that fuse the MET kinase domain to various fusion partners were described in six Spitz tumours 26 and are probably quite rare. Functional studies revealed that MET fusions constitutively activate the MAPK/ERK and PI3K/AKT/MTOR pathways.…”

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

“…Kinase inhibitors such as cabozantinib block oncogenic MET signalling and may provide treatment options for patients with metastatic tumours. 26 …”

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

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Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

et al. 2016

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Summary Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas conventional naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion, may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or reduce and alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour genomics and progression will refine the classification of melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

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Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

“…Kinase inhibitors such as cabozantinib block oncogenic MET signalling and may provide treatment options for patients with metastatic tumours. 26 …”

Section: Genetic Aberrations In Spitz Tumoursmentioning

confidence: 99%

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Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

et al. 2016

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“…A classic example of this is TRIM19, which is fused with retinoic acid receptor α (RARα) in acute PML disease (de Thé et al, 1991; Kakizuka et al, 1991). Furthermore, fusions between TRIM24 and B-Raf are found in liver cancer (Le Douarin et al, 1995), between TRIM27 and RET in papillary thyroid cancer (Hasegawa et al, 1996), and of TRIM4 with B-Raf in lung cancer (Zheng et al, 2014) or with MET in melanoma (Yeh et al, 2015). Among these, the TRIM19-RARα fusion protein is already known to be degraded by autophagy Wang et al, 2014), whereas clearance of TRIM19-RARα is a therapeutic target in acute PML disease (Nasr et al, 2008).…”

Section: Role Of Trim-directed Precision Autophagy In Diseasementioning

confidence: 99%

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

Kimura

Mandell

Deretić

2016

Journal of Cell Science

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Selective autophagy entails cooperation between target recognition and assembly of the autophagic apparatus. Target recognition is conducted by receptors that often recognize tags, such as ubiquitin and galectins, although examples of selective autophagy independent of these tags are emerging. It is less known how receptors cooperate with the upstream autophagic regulators, beyond the well-characterized association of receptors with Atg8 or its homologs, such as LC3B (encoded by MAP1LC3B), on autophagic membranes. The molecular details of the emerging role in autophagy of the family of proteins called TRIMs shed light on the coordination between cargo recognition and the assembly and activation of the principal autophagy regulators. In their autophagy roles, TRIMs act both as receptors and as platforms ('receptor regulators') for the assembly of the core autophagy regulators, such as ULK1 and Beclin 1 in their activated state. As autophagic receptors, TRIMs can directly recognize endogenous or exogenous targets, obviating a need for intermediary autophagic tags, such as ubiquitin and galectins. The receptor and regulatory features embodied within the same entity allow TRIMs to govern cargo degradation in a highly exact process termed 'precision autophagy'.

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Genomic Rearrangements in Unusual and Atypical Melanocytic Neoplasms

Wiesner

2016

JAMA Dermatol

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Activating MET kinase rearrangements in melanoma and Spitz tumours

Cited by 140 publications

References 48 publications

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

Precision autophagy directed by receptor regulators – emerging examples within the TRIM family

Genomic Rearrangements in Unusual and Atypical Melanocytic Neoplasms

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