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

• Published in: The Journal of clinical investigation Vol. 129; no. 9; pp. 3827 - 3832
• Main Authors: Sekine, Shigeki, Kiyono, Tohru, Ryo, Eijitsu, Ogawa, Reiko, Wakai, Susumu, Ichikawa, Hitoshi, Suzuki, Koyu, Arai, Satoru, Tsuta, Koji, Ishida, Mitsuaki, Sasajima, Yuko, Goshima, Naoki, Yamazaki, Naoya, Mori, Taisuke
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2019
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adult; Aged; Aged, 80 and over; Animals; Biomedical research; Cancer; Carcinoma - genetics; Carcinoma - metabolism; Concise Communication; Female; Fluorescence; Fluorescence in situ hybridization; Genes; Genes, Reporter; Genetic research; Genomes; HEK293 Cells; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Male; Mice; Middle Aged; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; NIH 3T3 Cells; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Polymerase chain reaction; Poroma - genetics; Poroma - metabolism; Proteins; Reverse transcription; Ribonucleic acid; RNA; RNA sequencing; Signal Transduction; Skin; Skin cancer; Sweat; Sweat gland; Sweat Gland Neoplasms - genetics; Sweat Gland Neoplasms - metabolism; Therapeutic applications; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription (Genetics); Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumorigenesis; Tumors; Yes-associated protein; Japan; Oncology; Dermatology; Oncogenes; Skin cancer
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci126185

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.