Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Zhaoming Li; Xudong Zhang; Weili Xue; Yanjie Zhang; Chaoping Li; Yue Song; Mei Mei; Lisha Lu; Yingjun Wang; Zhiyuan Zhou; Mengyuan Jin; Yangyang Bian; Lei Zhang; Xinhua Wang; Ling Li; Xin Li; Xiaorui Fu; Zhenchang Sun; Jingjing Wu; Feifei Nan; Yu Chang; Jiaqin Yan; Hui Yu; Xiaoyan Feng; Guannan Wang; Dandan Zhang; Xuefei Fu; Yuan Zhang; Ken H Young; Wencai Li; Mingzhi Zhang

doi:10.1038/s41467-019-12032-9

Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Nat Commun. 2019 Sep 16;10(1):4209. doi: 10.1038/s41467-019-12032-9.

Authors

Zhaoming Li^#^{1

2}, Xudong Zhang^#^{1

2}, Weili Xue^#^{1

3}, Yanjie Zhang^#^{1

3}, Chaoping Li^{1

3}, Yue Song^{1

3}, Mei Mei^{1

3}, Lisha Lu^{1

3}, Yingjun Wang^{1

3}, Zhiyuan Zhou^{1

3}, Mengyuan Jin^{1

3}, Yangyang Bian⁴, Lei Zhang^{1

2}, Xinhua Wang^{1

2}, Ling Li^{1

2}, Xin Li^{1

2}, Xiaorui Fu^{1

2}, Zhenchang Sun^{1

2}, Jingjing Wu^{1

2}, Feifei Nan^{1

2}, Yu Chang^{1

2}, Jiaqin Yan^{1

2}, Hui Yu^{1

2}, Xiaoyan Feng^{1

2}, Guannan Wang⁵, Dandan Zhang⁵, Xuefei Fu⁶, Yuan Zhang⁷, Ken H Young⁸, Wencai Li⁹, Mingzhi Zhang^{10

11}

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
² Lymphoma Diagnosis and Treatment Center of Henan Province, 450000, Zhengzhou, China.
³ Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
⁴ Medical Research Centre, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
⁵ Department of Pathology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
⁶ Novogene Bioinformatics Technology Co, Ltd, 38 Xueqing Road, 100083, Beijing, China.
⁷ The Academy of Medical Science of Zhengzhou University, 450052, Zhengzhou, China.
⁸ Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁹ Department of Pathology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China. wencailizzu@126.com.
¹⁰ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China. mingzhi_zhang@126.com.
¹¹ Lymphoma Diagnosis and Treatment Center of Henan Province, 450000, Zhengzhou, China. mingzhi_zhang@126.com.

^# Contributed equally.

Abstract

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations of GNAQ (encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaq^fl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients with GNAQ T96S mutations have inferior survival. Taken together, we identify recurrent somatic GNAQ T96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
GTP-Binding Protein alpha Subunits, Gq-G11 / genetics*
GTP-Binding Protein alpha Subunits, Gq-G11 / immunology
Humans
Lymphoma, T-Cell / genetics*
Lymphoma, T-Cell / immunology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation, Missense*
Natural Killer T-Cells / immunology

Substances

GTP-Binding Protein alpha Subunits, Gq-G11