Abstract 2220: Next-generation sequencing of the primary and recurrent tumors from patients with extranodal natural killer/T cell lymphoma
Authors: Cho William C. , Tan Kien Thiam , Ngan Roger K. , Cheuk Wah , Yang Yi-Ting , Chen Shu-Jen 
Published: July 2021

Abstract
Introduction: Nasal-type extranodal natural killer/T cell lymphoma (ENKTL) is an aggressive, EBV-associated tumor commonly found in the nasal cavity. It is more prevalent in patients in Asia and Latin America mainly affecting the extranodal sites. Upfront radiotherapy (RT) with or without chemotherapy is the mainstay of treatment but the patient response is variable. ENKTL is often resistant to conventional chemotherapy and early relapse is common. This study evaluated the mutational profiles of recurrent ENKTL for the mechanism of resistance and attempted to look for potential therapeutic targets.
Materials and Methods: This pilot study involved paired samples obtained from three patients with recurrent ENKTL. Next-generation sequencing was performed to investigate the gene alteration profiles of paired pre- and post-treatment recurrent tumor samples in these patients following chemoradiotherapy (CRT) or RT alone.
Results: A total of 55 variants was identified, with an average of 20 ± 5 variants per patient. Four genes were frequently mutated in the ENKTL samples, including MUC16 (100%), ARID1A (83%), ADAMTSL1 (67%), and KMT2C (50%). After CRT, case 1 developed local recurrence at nasal cavity within 46 months. The number of mutations in case 1 was nearly identical regardless of recurrent status, with only one acquired amplification (CTLA4) in the recurrent tumor. After RT alone, case 2 relapsed at nasal cavity and skin within 16 months. This patient harbored six mutations (ABCC2, FBXW7, FLT1, FOXL2, JAK1, and JAK3) and three deletions (BMPR1A, FAS, and PTEN) in the recurrent tumor, but not in the primary tumor. After RT alone, case 3 relapsed at nasal cavity and stomach within 42 months. Two mutations (FAT1 and NBN) and three amplifications (CDKN1B, HIST1H1C, and HIST1H1E) were only detected in the primary tumor of case 3, whereas one mutation (ARID2) and two amplifications (EZH2 and PIK3CG) were only identified in the recurrent tumor. On the other hand, two clinically relevant targets (TSC2 and RAD54L) were identified in case 2 and case 3, respectively. TSC2 is an FDA-recognized predictive marker for everolimus in central nervous system cancer and RAD54L is an FDA-recognized predictive marker for olaparib in prostate cancer.
Conclusion: Our data showed that MUC16, ARID1A and ADAMTSL1 were observed in more than half of nasal-type ENKTL. Additional mutations can be found in recurrent tumors but the relationship between the acquisition of new mutations and the treatment received was still poorly understood. TSC2 and RAD54L mutations were identified in some recurrent tumors which may serve as potential therapeutic targets for ENKTL. Despite the small sample size, NGS seems to be a powerful tool to shed light on the mutational landscape and biology of recurrent NKTCL.
Citation Format: William C. Cho, Kien Thiam Tan, Roger K. Ngan, Wah Cheuk, Yi-Ting Yang, Shu-Jen Chen. Next-generation sequencing of the primary and recurrent tumors from patients with extranodal natural killer/T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2220.