Functional annotation of the Hippo pathway somatic mutations in human cancers

• Published in: Nature communications 2024-11, Vol.15 (1), p.10106-18, Article 10106
• Main Authors: Han, Han, Huang, Zhen, Xu, Congsheng, Seo, Gayoung, An, Jeongmin, Yang, Bing, Liu, Yuhan, Lan, Tian, Yan, Jiachen, Ren, Shanshan, Xu, Yue, Xiao, Di, Yan, Jonathan K., Ahn, Claire, Fishman, Dmitry A., Meng, Zhipeng, Guan, Kun-Liang, Qi, Ruxi, Luo, Ray, Wang, Wenqi
• Format: Article
• Language: English
• Subjects: 13/106; 13/109; 13/95; 14/63; 38/39; 38/77; 45/23; 631/67/1244; 631/80/86; 82/1; 82/29; 82/58; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Annotations; Cancer; Cancer therapies; Cell Line, Tumor; Genes; Head & neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Hippo Signaling Pathway - genetics; Humanities and Social Sciences; Humans; Loss of Function Mutation; Meningioma; Mice; Missense mutation; multidisciplinary; Mutation; Mutation, Missense; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neurofibromin 2; Neurofibromin 2 - genetics; Neurofibromin 2 - metabolism; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Schwann cells; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Structure-function relationships; Tumors; Zinc finger proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54480-y

The Hippo pathway is commonly altered in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms. Interestingly, we reveal zinc-finger domain as an integral structure for MOB1 function, whose LOF mutations in head and neck cancer promote tumor growth. Moreover, the schwannoma/meningioma-derived NF2 LOF mutations not only inhibit its tumor suppressive function in the Hippo pathway, but also gain an oncogenic role for NF2 by activating the VANGL-JNK pathway. Collectively, our study not only offers a rich somatic mutation resource for investigating the Hippo pathway in human cancers, but also provides a molecular basis for Hippo-based cancer therapy. The Hippo signalling pathway is commonly mutated across cancer types. Here, the authors identify 85 loss-of-function missense mutations within Hippo signalling genes and highlight the mechanisms underpinning mutations in MOB1 and NF2.