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

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.