MOLECULAR CHARACTERIZATION OF EXTRANODAL NATURAL KILLER (NK)/T‐CELL LYMPHOMAS, NASAL TYPE FROM LATIN AMERICA
2017-06-01

Introduction: Extranodal Natural Killer/T (NK/T)-cell lymphoma, nasal type (ENKTCL) is a rare, aggressive type of non-Hodgkin lymphoma associated with Epstein-Barr virus (EBV). This lymphoma is more prevalent in Asians and Native American populations from Mexico and Central and South America. Recent studies from Asia have demonstrated recurrent mutations of various genes in ENKTCL; however, the overlap of mutations found in different studies/populations is rather low. This discrepancy may be due either to the technology used or the genetic background of the population analyzed that might imprint the mutational landscape. Most of the studies, so far, come from China, Japan and Korea and nothing is known about the mutational landscape in ENKTCL cases in Latin American. The aim of this study is to analyze by next generation sequencing (NGS) a large series of ENKTCL from Latin America collected in three National Cancer Institues (Mexico, Peru and Argentina) using an AmpliSeq Custom Panel including genes recurrently mutated in ENKTCL. This comprehensive genetic analysis aims to understand whether the different molecular results identified are associated with different ethnic backgrounds and how these mutations contribute to the pathogenesis of ENKTCL. Methods: We analyzed 111 cases (69 from Mexico, 27 from Peru and 15 from Argentina). In all cases H&E stain, CD56 and EBERS in situ hybridization were performed. Tumor DNA was isolated and only cases with DNA quality >300 bp were analyzed by NGS. Genes were selected from previously reported whole exome sequencing data from ENKTCL based on their frequency and potential biological significance. The AmpliSeq Custom Panel included the following genes: STAT3, STAT5B, JAK3, DDX3X, TP53, MGA, MSN and BCOR. The analysis was performed on the Ion Torrent PGM platform. Results: In total, 45 cases have been analyzed by NGS (29 from Mexico, 12 from Peru and 4 from Argentina). The mean average read depth of the NGS sequence analysis was 3405 (range 413-6187). 36 mutations were identified in 26 of 45 cases analyzed (58%). Mutations in STAT3, STAT5B and JAK3 were identified in 9 (20%), one (2%) and one (2%) cases, respectively. All together, 11 mutations (24%) affected the JAK-STAT pathway. Hotspot mutations G618R, Y640F and D661Y in the SH2 domain of STAT3were observed in the majority of the cases whereas the hotspot A573V of the JH2 domain of JAK3 was identified in one case. The second most frequent mutation was in the transcription co-repressor BCOR found in 7 cases (16%). DDX3X and TP53 mutations were detected in 5 (11%) and 4 (9%) cases, respectively. As has been reported, DDX3X and TP53 mutations were mutually exclusive, except for one case. MGA mutations were found in 6 cases (13%) and often concurrent with other genes (2 cases each STAT3 and BCOR). MSN mutations were identified in 3 cases (7%), 2 of which were concurrent with STAT3. From the 26 cases with mutations, 18 cases (69%) had only one mutation, 6 cases had 2 mutations (23%), and 2 cases had 3 mutations (8%) Comparison of the amount of mutated cases among the three Latin American countries revealed that Mexican cases are more frequently mutated compared to Peru and Argentina (65%, 42% and 50% respectively). TP53, DDX3X and MSN mutations were almost exclusively identified in the Mexican cases. Only one DDX3X mutation was present in a Peruvian case. The only JAK3 mutation identified was in a case from Argentina. Keywords: Epstein-Barr virus (EBV); non-Hodgkin lymphoma (NHL); T-cell lymphoma (TCL).