Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma - PubMed (original) (raw)

. 2019 May 30;129(9):3827-3832.

doi: 10.1172/JCI126185.

Tohru Kiyono 3 4, Eijitsu Ryo 2, Reiko Ogawa 2, Susumu Wakai 1, Hitoshi Ichikawa 5, Koyu Suzuki 6, Satoru Arai 7, Koji Tsuta 8, Mitsuaki Ishida 8, Yuko Sasajima 9, Naoki Goshima 10, Naoya Yamazaki 11, Taisuke Mori 1 2

Affiliations

Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma

Shigeki Sekine et al. J Clin Invest. 2019.

Abstract

Poroma is a benign skin tumor exhibiting terminal sweat gland duct differentiation. The present study aimed to explore the potential role of gene fusions in the tumorigenesis of poromas. RNA sequencing and reverse transcription PCR identified highly recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poromas (92/104 lesions, 88.5%) and their rare malignant counterpart, porocarcinomas (7/11 lesions, 63.6%). A WWTR1-NUTM1 fusion was identified in a single lesion of poroma. Fluorescent in-situ hybridization confirmed genomic rearrangements involving these genetic loci. Immunohistochemical staining could readily identify the YAP1 fusion products as nuclear expression of the N-terminal portion of YAP1 with a lack of the C-terminal portion. YAP1 and WWTR1, also known as YAP and TAZ, respectively, encode paralogous transcriptional activators of TEAD, which are negatively regulated by the Hippo signaling pathway. The YAP1 and WWTR1 fusions strongly transactivated a TEAD reporter and promoted anchorage-independent growth, confirming their tumorigenic roles. Our results demonstrate the frequent presence of transforming YAP1 fusions in poromas and porocarcinomas and suggest YAP1/TEAD-dependent transcription as a candidate therapeutic target against porocarcinoma.

Keywords: Dermatology; Oncogenes; Oncology; Skin cancer.

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1

Figure 1. Detection of YAP1 and WWTR1 fusions in poromas and porocarcinomas.

(A) Fusion gene transcripts detected in poromas and porocarcinomas. All of the MAML2-YAP1 fusions were associated with the reciprocal YAP1-MAML2 fusions. (B) Representative gel images of RT-PCR products. MAML2-YAP1 fusion transcripts were consistently associated with the reciprocal YAP1-MAML2 fusions. Many of the tumors expressed multiple transcriptional variants. ACTB served as a positive control. (C) Representative fluorescence in situ hybridization images. The detected fusion transcripts are indicated on the left of the respective images. Arrowheads, split signals. Arrows, fused signals.

Figure 2

Figure 2. Expression of YAP1 and NUTM1 in poromas, a porocarcinoma, and a squamous cell carcinoma.

Tumors with YAP1 fusions showed diffuse nuclear expression of the N-terminal region of YAP1 but lacked the expression of the C-terminal region. Squamous cell carcinoma showed nuclear and cytoplasmic staining with both N- and C-terminus antibodies. The diffuse nuclear expression of NUTM1 was exclusively observed in tumors with the YAP1-NUTM1 fusions. The anti-YAP1 N-terminus antibody, but not the C-terminus antibody, cross-reacts with the WWTR1. Scale bar: 100 μm.

Figure 3

Figure 3. Summary of fusion transcript expression, immunohistochemical results, and clinicopathological features of poroma and porocarcinoma.

Poroma (n = 104); porocarcinoma (n = 11). YAP1 immunohistochemistry (IHC) indicates cases with discordant expression of the N- and C-terminal regions.

Figure 4

Figure 4. Functional significance of YAP1 and WWTR1 fusions.

(A) Structures of the putative fusion gene products expressed in poromas and porocarcinomas. Arrows indicate fusion breakpoints. Notice that YAP1-MAML2, YAP1-NUTM1, and WWTR1-NUTM1 fusion gene products harbor a TEAD-binding domain derived from YAP1 or WWTR1 and a p300-binding domain derived from MAML2 or NUTM1. (B)Intracellular localization of YAP1 fusion gene products. The FLAG-tagged proteins were detected by immunofluorescence staining with nuclear staining using DAPI. Scale bars: 10 μm. (C) TEAD luciferase reporter assays on HEK293T cells transfected with doxycycline-inducible vectors. YAP1S127A and YAP15SA represent constitutively active mutants. The luciferase activity of EGFP-transfected cells in the absence of doxycycline was set at 1 to indicate relative luciferase activities. Data represent mean of triplicate measurements ± SD. (D) Soft agar colony formation assay of NIH3T3 cells expressing the fusion transgenes. NIH3T3 cells were transduced with doxycycline-inducible retrovirus vectors to express the respective transgenes and subjected to a soft agar colony formation assay in the presence of doxycycline. None of the clones formed colonies in the absence of doxycycline. Scale bar: 200 μm.

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