Frequent mutations in HLA and related genes in extranodal NK/T cell lymphomas

Abstract

Extranodal NK/T cell lymphomas (ENKTCLs) are aggressive Epstein–Barr virus-associated T/NK neoplasms that predominantly affect Asians. To explore the causative somatic events, we conducted a comprehensive genetic analysis of 19 ENKTCL patients by whole-genome (N = 2), whole-exome (N = 16), and targeted sequencing (N = 15). Commonly deregulated gene pathways in ENKTCLs included epigenetic modifiers (58%, 11/19) followed by human leukocyte antigens (HLAs) and related genes including HLA-A, B2M, TAP1, CD274, and PDCD1LG2 (32%, 6/19), and JAK-STAT pathway (26%, 5/19). Conspicuously, loss-of-function mutations in HLA-A were recurrently identified in ENKTCLs (16%, 3/19). HLA protein expression was examined by immunohistochemistry in 16 patients and lower expression was associated with advanced stages at presentation (p = .007). In conclusion, the defective antigen presenting pathway is common and related to disease progression, suggesting immune escape as a pathogenic mechanism of ENKTCLs.

Keywords:

• HLA
• extranodal NK/T cell lymphomas
• Epstein–Barr virus

Disclosure statement

The authors have no conflicts of interest to declare.

Author contributions

C.P. collected samples and clinical data, extracted DNA, performed WES, analyzed data, and wrote the manuscript. Y.T. extracted DNA, performed WES, analyzed data, and wrote the manuscript. H.M. supervised, conceptualized the research, and wrote the manuscript. N.K. analyzed WES data. N.T. analyzed HLA immunostaining results. T.A. reviewed pathology reports. W.S. prepared and extracted DNA. Ha.M. provided PD-L1 data. K.W., P.L., S.K., K.I., and U.B. provided patient samples and clinical data. Y.S., K.C., H.T., and S.M. analyzed WES data. K.Y. analyzed WES, WGS, targeted sequencing data, and wrote the manuscript. P.R. and S.O. conceptualized the overall research and wrote the manuscript. All authors read and approved the final manuscript.

Additional information

Funding

This work was supported by the Thailand Research Fund (RSA6080011; C.P.), and Research Unit in Translational Hematology, Chulalongkorn University, Bangkok, Thailand (U.B.). Grants-in-Aid from the Ministry of Health, Labor and Welfare of Japan (Health and Labour Sciences Research Expenses for Commission and Applied Research for Innovative Treatment of Cancer), JSPS KAKENHI (15H05909) and Grant for project for cancer research and therapeutics evolution (P-CREATE) from AMED (JP16cm0106501 and 17cm0106501h0002).