Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma
Authors: Ito Yuta , Marouf Amira , Kogure Yasunori , Koya Junji , Liévin Raphaël , Bruneau Julie , Tabata Mariko , Saito Yuki , Shingaki Sumito , Yuasa Mitsuhiro , Yamaguchi Kentaro , Murakami Koichi , Weil Robert , Vavasseur Manon , Andrieu Guillaume P. , Latiri Mehdi , Veleanu Layla , Dussiot Michaël , André Isabelle , Joshi Akshay , Lagresle-Peyrou Chantal , Magerus Aude , Chaubard Sammara , Lavergne David , Bachy Emmanuel , Brunet Erika , Fataccioli Virginie , Brouzes Chantal , Laurent Camille , de Leval Laurence , Traverse-Glehen Alexandra , Bossard Céline , Parrens Marie , Meignin Véronique , Philippe Laure , Rossignol Julien , Suarez Felipe , Michot Jean-Marie , Tournilhac Olivier , Damaj Gandhi , Lemonnier François , Bôle-Feysot Christine , Nitschké Patrick , Tesson Bruno , Laurent Cécile , Molina Thierry , Asnafi Vahid , Watatani Yosaku , Chiba Kenichi , Okada Ai , Shiraishi Yuichi , Tsukita Sachiko , Izutsu Koji , Miyoshi Hiroaki , Ohshima Koichi , Sakata Seiji , Dobashi Akito , Takeuchi Kengo , Sanada Masashi , Gaulard Philippe , Jaccard Arnaud , Ogawa Seishi , Hermine Olivier , Kataoka Keisuke , Couronné Lucile 
Published: April 2024

Abstract
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein–Barr virus (EBV)–related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL.
Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition.