A Novel Fusion of TPR and ALK in Lung Adenocarcinoma

Choi, Yoon‐La; Lira, Maruja E.; Hong, Mineui; Kim, Ryong Nam; Choi, Seong Hee; Song, Ji-Young; Pandy, Kinnari; Mann, Derrick L.; Stahl, Joshua; Peckham, Heather E.; Zheng, Zongli; Han, Joungho; Mao, Mao; Kim, Young Tae

doi:10.1097/jto.0000000000000093

Cited by 77 publications

(46 citation statements)

References 12 publications

(11 reference statements)

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“…An NPM1-ALK fusion resulted from a t(2;5) translocation; this translocation is found in a majority of anaplastic large cell lymphomas 25 . A similar TPR-ALK fusion to that which we identified was recently described in lung adenocarcinoma 26 . The identification of a CLIP1-ALK fusion supports the hypothesis that the N-terminal partners of kinase fusions may be interchangeable within Spitz tumors as CLIP1 also partners with ROS1 in Spitz tumors 7 .…”

Section: Discussionsupporting

confidence: 82%

Clinical, Histopathologic, and Genomic Features of Spitz Tumors With ALK Fusions

Yeh

Fouchardière²,

Pissaloux³

et al. 2015

American Journal of Surgical Pathology

129

146

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Activating kinase fusions have recently been described as early oncogenic events that are mutually exclusive with HRAS and BRAF mutations in Spitz tumors. Here, we report a series of 32 Spitz tumors with ALK fusions (6 Spitz nevi, 22 atypical Spitz tumors, and 4 Spitzoid melanomas) in patients ranging from 5 months to 64 years (median=12 y) of age. The tumors typically presented as exophytic papules on the extremities and were occasionally darkly pigmented. In addition to ALK fusions previously described in other tumor types (NPM1-ALK, TPR-ALK) we identified 2 novel ALK fusions (CLIP1-ALK and GTF3C2-ALK) in our cohort of Spitz tumors. Array comparative genomic hybridization of 19 of these tumors demonstrated a high frequency of chromosome 2 aberrations (where ALK resides, 63%) and chromosome 1p loss in 37% of the cases. Spitz tumors with ALK fusions demonstrated unique histopathologic features. Clefts and small vesicle-like spaces were arrayed between plump spindled melanocytes with fibrillar cytoplasm and enlarged nuclei. These melanocytes were typically arrayed in elongated and fusiform nests with radial orientation. The tumors often had extension into the dermis or subcutis with a wedge-shaped or bulbous lower border (45% and 17% respectively). An infiltrative growth pattern was often present at the periphery of the tumor and was highlighted by ALK immunohistochemistry. In conclusion, Spitz tumors with ALK rearrangement show distinct histopathologic features that should aid in improving classification of these diagnostically challenging tumors.

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Section: Discussionsupporting

confidence: 82%

Clinical, Histopathologic, and Genomic Features of Spitz Tumors With ALK Fusions

Yeh

Fouchardière²,

Pissaloux³

et al. 2015

American Journal of Surgical Pathology

129

146

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“…Some novel fusion genes of ALK rearrangement have recently been published but their clinical relevance is not yet clear [3,4]. The coexpression of different ALK splicing isoforms were presented in NSCLC and the results indicate that the response to crizotinib may also depend on the ALK splicing type [5].…”

Section: Discussionmentioning

confidence: 94%

Identification of atypical ATRNL1 insertion to EML4-ALK fusion gene in NSCLC

et al. 2015

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“…With the discovery of TPR-MET as fusion kinase almost 30 years ago, it has become an important prototype to investigate the mechanism of RTK-derived oncogene generation by translocation. Subsequently, several other TPR based fusion kinases were reported, including the RTK fusion kinases TPR-TRK1 (Greco et al, 1992), TPR-ALK (Choi et al, 2014), and TPR-FGFR1(Malli et al, 2016) and the serine/threonine fusion kinase TPR-RAF (King et al, 1988)…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

et al. 2017

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Summary The nuclear pore complex subunit TPR is found in at least five different oncogenic fusion kinases, including TPR-MET, yet how TPR fusions promote activation of kinases and their oncogenic activities remains poorly understood. Here we report the crystal structure of TPR(2-142), the MET fusion partner of oncogenic TPR-MET. TPR(2-142) contains a continuous 124-residue α-helix that forms an anti-parallel tetramer from two leucine zipper-containing parallel coiled coils. Remarkably, single mutations cause strikingly different conformations of the coiled coil, indicating its highly dynamic nature. We further show that fusion of TPR(2-142) to the MET intracellular domain strongly and selectively stabilizes the αG-helix of the MET kinase domain and mutations of only the TPR leucine zipper residues at the junction to MET, but not other leucine zipper residues, abolish kinase activation. Together, these results provide critical insight into the TPR structure and its ability to induce dimerization and activation of fusion kinases.

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A Novel Fusion of TPR and ALK in Lung Adenocarcinoma

Cited by 77 publications

References 12 publications

Clinical, Histopathologic, and Genomic Features of Spitz Tumors With ALK Fusions

Clinical, Histopathologic, and Genomic Features of Spitz Tumors With ALK Fusions

Identification of atypical ATRNL1 insertion to EML4-ALK fusion gene in NSCLC

Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

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