Running title: Gene status improves risk stratification of ENKTL

NEOPLASMA accepted, ahead of print version; 1 Cite article as https://doi.org/10.4149/neo_2020_190307N194 2 3 Running title: Gene status improves risk stratification of ENKTL 4 5 KMT2D and TP53 mutation status improve the prognostic value of the International Prognostic 6 Index (IPI) stratification in ENKTL patients 7 8 Y. GAO*, Y. LI*, G. MA, G. ZHAO, H. LIU 9 10 Department of Hematology, Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 11 China 12 13 *Correspondence: ydsygao@sina.com, 419136407@qq.com 14 15 Extranodal NK/T-cell lymphoma nasal type (ENKTL) is a subtype of T cell lymphoma with poor 16 prognosis. In this study, we designed a new prognostic model specifically for ENKTL to improve the 17 risk stratification. In 29 ENKTL patients, we screened mutations in 9 ENKTL-associated genes using 18 next-generation sequencing (NGS). We have found that mutated KMT2D was associated with the 19 inferior overall survival (OS) and progression free survival (PFS) and KMT2D or TP53 mutations 20 were associated with higher mortality rate. Moreover, the difference in PFS among different 21 stratifications was not significant using the International Prognostic Index (IPI) alone, but was 22 significant after the mutation status of KMT2D and TP53 were incorporated into the IPI model, 23 forming a harmonious risk stratification reflecting the clinical features and genetic information of 24 ENKTL. In summary, we demonstrate that the prognostic value of the IPI system can be enhanced by 25 integrating the status of genetic mutations. 26 27

[1]  N. Sharma,et al.  KMT2D Mutation Is Associated With Poor Prognosis in Non–Small‐Cell Lung Cancer , 2018, Clinical lung cancer.

[2]  S. Chanock,et al.  Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma , 2018, British journal of haematology.

[3]  T. Noda,et al.  TP53 and OSBPL10 alterations in diffuse large B-cell lymphoma: prognostic markers identified via exome analysis of cases with extreme prognosis , 2018, Oncotarget.

[4]  Roland Schmitz,et al.  Genetics and Pathogenesis of Diffuse Large B‐Cell Lymphoma , 2018, The New England journal of medicine.

[5]  Quentin Liu,et al.  Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma , 2018, Nature Medicine.

[6]  Juan F. García,et al.  Analysis of the mutational landscape of classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic targets , 2017, Oncotarget.

[7]  S. Swerdlow.  WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues , 2017 .

[8]  Wen-Qi Jiang,et al.  Prognostic role of ABO blood type in patients with extranodal natural killer/T cell lymphoma, nasal type: a triple-center study , 2017, Chinese journal of cancer.

[9]  Kyudong Han,et al.  Mutational Analysis of Extranodal NK/T-Cell Lymphoma Using Targeted Sequencing with a Comprehensive Cancer Panel , 2016, Genomics & informatics.

[10]  J. Fitzgibbon,et al.  Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma. , 2016, Cancer research.

[11]  K. Mills,et al.  Inter-Laboratory Evaluation of a Next-Generation Sequencing Panel for Acute Myeloid Leukemia , 2016, Molecular Diagnosis & Therapy.

[12]  K. Sakamoto,et al.  Frequent BCOR aberrations in extranodal NK/T‐Cell lymphoma, nasal type , 2016, Genes, chromosomes & cancer.

[13]  A. Tefferi,et al.  Myelodysplastic syndromes: Contemporary review and how we treat , 2016, American journal of hematology.

[14]  O. Elemento,et al.  The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development , 2015, Nature Medicine.

[15]  Robert Kridel,et al.  Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. , 2015, The Lancet. Oncology.

[16]  K. Basso,et al.  Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis , 2015, Nature Medicine.

[17]  Christina N. Vallianatos,et al.  Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders. , 2015, Epigenomics.

[18]  A. Dingwall,et al.  The cancer COMPASS: navigating the functions of MLL complexes in cancer. , 2015, Cancer genetics.

[19]  Seungbok Lee,et al.  Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type , 2015, Oncotarget.

[20]  Jie He,et al.  Annual report on status of cancer in China, 2011. , 2015, Chinese journal of cancer research = Chung-kuo yen cheng yen chiu.

[21]  W. Xue,et al.  Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma , 2014, Nature Genetics.

[22]  A. Levine,et al.  Tumor-Associated Mutant p53 Drives the Warburg Effect , 2013, Nature Communications.

[23]  R. McLendon,et al.  KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation , 2013, Oncotarget.

[24]  U. Moll,et al.  Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis , 2013, Cell Death and Differentiation.

[25]  Y. Kwong,et al.  SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group. , 2012, Blood.

[26]  John D Pfeifer,et al.  Targeted next generation sequencing of clinically significant gene mutations and translocations in leukemia , 2012, Modern Pathology.

[27]  R. Suzuki.  NK/T-Cell Lymphomas: Pathobiology, Prognosis and Treatment Paradigm , 2012, Current Oncology Reports.

[28]  Benjamin J. Raphael,et al.  The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer , 2016 .

[29]  Eric S. Lander,et al.  Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing , 2012, Proceedings of the National Academy of Sciences.

[30]  Steven J. M. Jones,et al.  Frequent mutation of histone modifying genes in non-Hodgkin lymphoma , 2011, Nature.

[31]  Raul Rabadan,et al.  Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma , 2011, Nature Genetics.

[32]  B. Bernstein,et al.  Role for Dpy-30 in ES Cell-Fate Specification by Regulation of H3K4 Methylation within Bivalent Domains , 2011, Cell.

[33]  P. Cheng,et al.  Nasal natural killer/T-cell lymphoma , 2010, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[34]  T. Tsuzuki,et al.  Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma, nasal type. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[35]  Natarajan Ganesan,et al.  Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon , 2010, Cancer Cell International.

[36]  Varda Rotter,et al.  When mutants gain new powers: news from the mutant p53 field , 2009, Nature Reviews Cancer.

[37]  D. Weisenburger,et al.  Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. , 2009, Blood.

[38]  T. Iwakuma,et al.  The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. , 2008, Genes & development.

[39]  T. Yoshino,et al.  [Extranodal NK/T-cell lymphoma, nasal type]. , 2007, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[40]  Yili Yin,et al.  p53 stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products , 2002, Nature Cell Biology.

[41]  H. Hoefler,et al.  p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease. , 2001, The American journal of pathology.

[42]  R. Greil,et al.  Epstein-Barr virus-associated extranodal NK/T-cell lymphoma, nasal type of the hypopharynx, in a renal allograft recipient: case report and review of literature. , 2001, Human pathology.

[43]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[44]  S. Friend,et al.  Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M Tubiana,et al.  Report of the Committee on Hodgkin's Disease Staging Classification. , 1971, Cancer research.

[46]  S. H. Lee,et al.  Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability. , 2013, Neoplasma.