Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma

Yuta Ito^{1

2}, Amira Marouf³, Yasunori Kogure¹, Junji Koya¹, Raphaël Liévin³, Julie Bruneau^{3

4}, Mariko Tabata^{1

5}, Yuki Saito^{1

6}, Sumito Shingaki¹, Mitsuhiro Yuasa^{1

7}, Kentaro Yamaguchi^{1

8}, Koichi Murakami^{1

8}, Robert Weil⁹, Manon Vavasseur³, Guillaume P Andrieu^{10

11}, Mehdi Latiri^{10

11}, Layla Veleanu^{10

11}, Michaël Dussiot³, Isabelle André¹², Akshay Joshi¹², Chantal Lagresle-Peyrou¹³, Aude Magerus¹⁴, Sammara Chaubard¹⁵, David Lavergne¹⁵, Emmanuel Bachy^{16

17}, Erika Brunet¹⁸, Virginie Fataccioli^{19

20}, Chantal Brouzes^{10

11}, Camille Laurent^{21

22}, Laurence de Leval²³, Alexandra Traverse-Glehen²⁴, Céline Bossard²⁵, Marie Parrens²⁶, Véronique Meignin²⁷, Laure Philippe²⁸, Julien Rossignol^{3

29}, Felipe Suarez^{3

29}, Jean-Marie Michot³⁰, Olivier Tournilhac³¹, Gandhi Damaj³², François Lemonnier^{20

33}, Christine Bôle-Feysot³⁴, Patrick Nitschké³⁵, Bruno Tesson³⁶, Cécile Laurent³⁶, Thierry Molina^{3

4}, Vahid Asnafi^{10

11}, Yosaku Watatani³⁷, Kenichi Chiba³⁸, Ai Okada³⁸, Yuichi Shiraishi³⁸, Sachiko Tsukita³⁹, Koji Izutsu^{40

41}, Hiroaki Miyoshi⁴², Koichi Ohshima⁴², Seiji Sakata^{43

44

45}, Akito Dobashi^{43

44

45}, Kengo Takeuchi^{43

44

45}, Masashi Sanada⁴⁶, Philippe Gaulard^{19

20}, Arnaud Jaccard¹⁵, Seishi Ogawa^{37

47

48}, Olivier Hermine^{3

29}, Keisuke Kataoka^{1

8}, Lucile Couronné^{3

11}

Affiliations

¹ Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
² Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
³ Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR_S 1163, Imagine Institute, Université Paris Cité, Paris, France.
⁴ Pathology Department, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
⁵ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
⁷ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁸ Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
⁹ Sorbonne Universités, Institut National de la Santé et de la Recherche Médiicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France.
¹⁰ INSERM UMR_S 1151, Necker Enfants Malades Institute (INEM), Université Paris Cité, Paris, France.
¹¹ Laboratory of Onco-Hematology, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
¹² Human Lymphohematopoiesis Lab, Université Paris Cité, Imagine Institute, INSERM UMR_S 1163, Paris, France.
¹³ Biotherapy Clinical Investigation Center, Université Paris Cité, Imagine Institute, INSERM CIC 1416, Assistance Publique-Hopitaux de Paris, Paris, France.
¹⁴ Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Université Paris Cité, Imagine Institute, INSERM UMR_S 1163, Paris, France.
¹⁵ Hematology Department, Limoges University Hospital, Limoges, France.
¹⁶ Hematology Department, Lyon Civils Hospices, Lyon, France.
¹⁷ Lymphoma Immuno-Biology (LIB) Team, Université Claude Bernard Lyon 1, Lyon, France.
¹⁸ Laboratory of the Genome Dynamics in the Immune System, Équipe Labéllisée La Ligue Contre Le Cancer, Université Paris Cité, Paris Saclay University, INSERM UMR_S 1163, Imagine Institute, Paris, France.
¹⁹ Pathology Department, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Créteil, France.
²⁰ INSERM U955, Mondor Institute for Biomedical Research, Paris-Est Créteil University, Créteil, France.
²¹ Department of Pathology, Cancer University Institute of Toulouse Oncopole, Toulouse, France.
²² Cancer Research Center of Toulouse, INSERM UMR 1037, ERL5294 CNRS, Toulouse III-Paul-Sabatier University, Toulouse, France.
²³ Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland.
²⁴ Department of Pathology, Lyon Sud Hospital, Claude Bernard Lyon-1 University, Pierre-Bénite, France.
²⁵ Department of Pathology, Nantes University Hospital, Nantes, France.
²⁶ Department of Pathology, Bordeaux University Hospital, Bordeaux University, Bordeaux, France.
²⁷ Pathology Department, Saint Louis Hospital, Université Paris Cité, Paris, France.
²⁸ Department of Hematology, Annecy Genevois Hospital, Epagny Metz-Tessy, France.
²⁹ Hematology Department, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
³⁰ Drug Development Department, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France.
³¹ Department of Hematology, Clermont-Ferrand University Hospital, Clermont Auvergne University, Clermont-Ferrand, France.
³² Department of Hematology, Caen University Hospital, Normandy University, Caen, France.
³³ Hematology Department, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Créteil, France.
³⁴ Genomics Core Facility, Imagine Institute-SFR Necker, INSERM U1163 and INSERM US24/CNRS UAR3633, Université Paris Cité, Paris, France.
³⁵ INSERM UMR_S 1163, Bioinformatics Platform, Imagine Institute, Université Paris Cité, Paris, France.
³⁶ Bioinformatics Department, LYSARC, Pierre-Bénite, France.
³⁷ Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
³⁸ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
³⁹ Advanced Comprehensive Research Organization (ACRO), Teikyo University, Tokyo, Japan.
⁴⁰ Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
⁴¹ Department of Hematology, Toranomon Hospital, Tokyo, Japan.
⁴² Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
⁴³ Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴⁴ Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴⁵ Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴⁶ Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
⁴⁷ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
⁴⁸ Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.

PMID: 38657099
DOI: 10.1158/0008-5472.CAN-24-0132

Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma

Yuta Ito et al. Cancer Res. 2024.

. 2024 Jul 2;84(13):2181-2201.

doi: 10.1158/0008-5472.CAN-24-0132.

Authors

Affiliations

¹ Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
² Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
³ Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR_S 1163, Imagine Institute, Université Paris Cité, Paris, France.
⁴ Pathology Department, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
⁵ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Gastroenterology, Keio University School of Medicine, Tokyo, Japan.
⁷ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁸ Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
⁹ Sorbonne Universités, Institut National de la Santé et de la Recherche Médiicale (INSERM, UMR1135), Centre National de la Recherche Scientifique (CNRS, ERL8255), Centre d'Immunologie et des Maladies Infectieuses CMI, Paris, France.
¹⁰ INSERM UMR_S 1151, Necker Enfants Malades Institute (INEM), Université Paris Cité, Paris, France.
¹¹ Laboratory of Onco-Hematology, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
¹² Human Lymphohematopoiesis Lab, Université Paris Cité, Imagine Institute, INSERM UMR_S 1163, Paris, France.
¹³ Biotherapy Clinical Investigation Center, Université Paris Cité, Imagine Institute, INSERM CIC 1416, Assistance Publique-Hopitaux de Paris, Paris, France.
¹⁴ Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Université Paris Cité, Imagine Institute, INSERM UMR_S 1163, Paris, France.
¹⁵ Hematology Department, Limoges University Hospital, Limoges, France.
¹⁶ Hematology Department, Lyon Civils Hospices, Lyon, France.
¹⁷ Lymphoma Immuno-Biology (LIB) Team, Université Claude Bernard Lyon 1, Lyon, France.
¹⁸ Laboratory of the Genome Dynamics in the Immune System, Équipe Labéllisée La Ligue Contre Le Cancer, Université Paris Cité, Paris Saclay University, INSERM UMR_S 1163, Imagine Institute, Paris, France.
¹⁹ Pathology Department, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Créteil, France.
²⁰ INSERM U955, Mondor Institute for Biomedical Research, Paris-Est Créteil University, Créteil, France.
²¹ Department of Pathology, Cancer University Institute of Toulouse Oncopole, Toulouse, France.
²² Cancer Research Center of Toulouse, INSERM UMR 1037, ERL5294 CNRS, Toulouse III-Paul-Sabatier University, Toulouse, France.
²³ Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland.
²⁴ Department of Pathology, Lyon Sud Hospital, Claude Bernard Lyon-1 University, Pierre-Bénite, France.
²⁵ Department of Pathology, Nantes University Hospital, Nantes, France.
²⁶ Department of Pathology, Bordeaux University Hospital, Bordeaux University, Bordeaux, France.
²⁷ Pathology Department, Saint Louis Hospital, Université Paris Cité, Paris, France.
²⁸ Department of Hematology, Annecy Genevois Hospital, Epagny Metz-Tessy, France.
²⁹ Hematology Department, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Paris, France.
³⁰ Drug Development Department, Gustave Roussy Institute, Paris-Saclay University, Villejuif, France.
³¹ Department of Hematology, Clermont-Ferrand University Hospital, Clermont Auvergne University, Clermont-Ferrand, France.
³² Department of Hematology, Caen University Hospital, Normandy University, Caen, France.
³³ Hematology Department, Henri Mondor University Hospital, Assistance Publique - Hôpitaux de Paris (APHP), Créteil, France.
³⁴ Genomics Core Facility, Imagine Institute-SFR Necker, INSERM U1163 and INSERM US24/CNRS UAR3633, Université Paris Cité, Paris, France.
³⁵ INSERM UMR_S 1163, Bioinformatics Platform, Imagine Institute, Université Paris Cité, Paris, France.
³⁶ Bioinformatics Department, LYSARC, Pierre-Bénite, France.
³⁷ Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
³⁸ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
³⁹ Advanced Comprehensive Research Organization (ACRO), Teikyo University, Tokyo, Japan.
⁴⁰ Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
⁴¹ Department of Hematology, Toranomon Hospital, Tokyo, Japan.
⁴² Department of Pathology, Kurume University School of Medicine, Kurume, Japan.
⁴³ Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴⁴ Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴⁵ Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴⁶ Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
⁴⁷ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.
⁴⁸ Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.

PMID: 38657099
DOI: 10.1158/0008-5472.CAN-24-0132

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.

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Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma

Affiliations

Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma

Authors

Affiliations

Abstract

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous