Recurrent GNAQ Mutation Encoding T96S in Natural Killer/T Cell Lymphoma

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Sep 19

PMID 31527657

Citations 21

Authors

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

Affiliations

Soon will be listed here.

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), 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.

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References

Lim S, Hee S, Quek R, Cheng Lim L, Yap S, Loong E . Comparative analysis of extra-nodal NK/T-cell lymphoma and peripheral T-cell lymphoma: significant differences in clinical characteristics and prognosis. Eur J Haematol. 2007; 80(1):55-60. DOI: 10.1111/j.1600-0609.2007.00978.x. View

Smith K, Yadav V, Pei S, Pollyea D, Jordan C, De S . SomVarIUS: somatic variant identification from unpaired tissue samples. Bioinformatics. 2015; 32(6):808-13. DOI: 10.1093/bioinformatics/btv685. View

Yamaguchi M, Suzuki R, Oguchi M . Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type. Blood. 2018; 131(23):2528-2540. DOI: 10.1182/blood-2017-12-791418. View

Gong J, Maki G, Klingemann H . Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia. 1994; 8(4):652-8. View

Nava V, Jaffe E . The pathology of NK-cell lymphomas and leukemias. Adv Anat Pathol. 2004; 12(1):27-34. DOI: 10.1097/01.pap.0000151318.34752.80. View

Tse E, Kwong Y . How I treat NK/T-cell lymphomas. Blood. 2013; 121(25):4997-5005. DOI: 10.1182/blood-2013-01-453233. View

Yamaguchi M, Oguchi M, Suzuki R . Extranodal NK/T-cell lymphoma: Updates in biology and management strategies. Best Pract Res Clin Haematol. 2018; 31(3):315-321. DOI: 10.1016/j.beha.2018.07.002. View

McCarty Jr K, Miller L, Cox E, Konrath J, McCarty Sr K . Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med. 1985; 109(8):716-21. View

Chan J, Ng A, Cheng C, Nairismagi M, Venkatesh B, Cheah D . Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma. Blood Cancer J. 2018; 8(11):111. PMC: 6232147. DOI: 10.1038/s41408-018-0149-5. View

10.

Wang D, Zhang Y, He Y, Li Y, Lund F, Shi G . The deficiency of Gαq leads to enhanced T-cell survival. Immunol Cell Biol. 2014; 92(9):781-90. DOI: 10.1038/icb.2014.53. View

11.

Forbes S, Bhamra G, Bamford S, Dawson E, Kok C, Clements J . The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet. 2008; Chapter 10:Unit 10.11. PMC: 2705836. DOI: 10.1002/0471142905.hg1011s57. View

12.

Laurini J, Perry A, Boilesen E, Diebold J, Maclennan K, Muller-Hermelink H . Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases. Blood. 2012; 120(24):4795-801. DOI: 10.1182/blood-2012-07-440073. View

13.

Barrionuevo C, Zaharia M, Martinez M, Taxa L, Misad O, Moscol A . Extranodal NK/T-cell lymphoma, nasal type: study of clinicopathologic and prognosis factors in a series of 78 cases from Peru. Appl Immunohistochem Mol Morphol. 2007; 15(1):38-44. DOI: 10.1097/01.pai.0000205062.27174.56. View

14.

Jiang L, Gu Z, Yan Z, Zhao X, Xie Y, Zhang Z . Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma. Nat Genet. 2015; 47(9):1061-6. DOI: 10.1038/ng.3358. View

15.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

16.

Gualco G, Domeny-Duarte P, Chioato L, Barber G, Natkunam Y, Bacchi C . Clinicopathologic and molecular features of 122 Brazilian cases of nodal and extranodal NK/T-cell lymphoma, nasal type, with EBV subtyping analysis. Am J Surg Pathol. 2011; 35(8):1195-203. DOI: 10.1097/PAS.0b013e31821ec4b5. View

17.

Lee S, Park H, Kang S, Kim S, Hwang J, Lee S . Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type. Oncotarget. 2015; 6(19):17764-76. PMC: 4627344. DOI: 10.18632/oncotarget.3776. View

18.

Jaccard A, Gachard N, Marin B, Rogez S, Audrain M, Suarez F . Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2010; 117(6):1834-9. DOI: 10.1182/blood-2010-09-307454. View

19.

OHayre M, Inoue A, Kufareva I, Wang Z, Mikelis C, Drummond R . Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the Gα13/RhoA axis in B cells. Oncogene. 2015; 35(29):3771-80. PMC: 4885800. DOI: 10.1038/onc.2015.442. View

20.

Barren B, Artemyev N . Mechanisms of dominant negative G-protein alpha subunits. J Neurosci Res. 2007; 85(16):3505-14. DOI: 10.1002/jnr.21414. View