Soheil Zorofchian1, Hanadi El-Achi1, Yuanqing Yan2, Yoshua Esquenazi3, Leomar Y Ballester4,5. 1. Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, 6431 Fannin St., MSB 2.136, Houston, TX, 77030, USA. 2. Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center, 6431 Fannin St., MSB 2.136, Houston, TX, 77030, USA. 3. Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center, 6431 Fannin St., MSB 2.136, Houston, TX, 77030, USA. Yoshua.EsquenaziLevy@uth.tmc.edu. 4. Department of Pathology and Laboratory Medicine, University of Texas Health Science Center, 6431 Fannin St., MSB 2.136, Houston, TX, 77030, USA. Leomar.Y.Ballester@uth.tmc.edu. 5. Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center, 6431 Fannin St., MSB 2.136, Houston, TX, 77030, USA. Leomar.Y.Ballester@uth.tmc.edu.
Abstract
PURPOSE: Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma that affects the central nervous system (CNS). Although previous studies have reported the most common mutated genes in PCNSL, including MYD88 and CD79b, our understanding of genetic characterizations in primary CNS lymphomas is limited. The aim of this study was to perform a retrospective analysis investigating the most frequent mutation types, and their frequency, in PCNSL. METHODS: Fifteen patients with a diagnosis of PCNSL from our institution were analyzed for mutations in 406 genes and rearrangements in 31 genes by next generation sequencing (NGS). RESULTS: Missense mutations were identified as the most common mutation type (32%) followed by frame shift mutations (23%). The highest mutation rate was reported in the MYD88 (33.3%), CDKN2A/B (33.3%), and TP53 (26.7%) genes. Intermediate tumor mutation burden (TMB) and high TMB was detected in 13.3% and 26.7% of PCNSL, respectively. The most frequent gene rearrangement involved the IGH-BCL6 genes (20%). CONCLUSIONS: This study shows the most common genetic alterations in PCNSL as determined by a commercial next generation sequencing assay. MYD88 and CD79b are frequently mutated in PCNSL, IGH-BCL6 is the most frequent gene rearrangement and approximately 1/4 of cases show a high TMB. Mutations in multiple genes, in addition to high TMB and gene rearrangements, highlights the complex molecular heterogeneity of PCNSL. Knowledge about genetic alterations in PCNSL can inform the development of novel targets for diagnosis and treatment.
PURPOSE:Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma that affects the central nervous system (CNS). Although previous studies have reported the most common mutated genes in PCNSL, including MYD88 and CD79b, our understanding of genetic characterizations in primary CNS lymphomas is limited. The aim of this study was to perform a retrospective analysis investigating the most frequent mutation types, and their frequency, in PCNSL. METHODS: Fifteen patients with a diagnosis of PCNSL from our institution were analyzed for mutations in 406 genes and rearrangements in 31 genes by next generation sequencing (NGS). RESULTS: Missense mutations were identified as the most common mutation type (32%) followed by frame shift mutations (23%). The highest mutation rate was reported in the MYD88 (33.3%), CDKN2A/B (33.3%), and TP53 (26.7%) genes. Intermediate tumor mutation burden (TMB) and high TMB was detected in 13.3% and 26.7% of PCNSL, respectively. The most frequent gene rearrangement involved the IGH-BCL6 genes (20%). CONCLUSIONS: This study shows the most common genetic alterations in PCNSL as determined by a commercial next generation sequencing assay. MYD88 and CD79b are frequently mutated in PCNSL, IGH-BCL6 is the most frequent gene rearrangement and approximately 1/4 of cases show a high TMB. Mutations in multiple genes, in addition to high TMB and gene rearrangements, highlights the complex molecular heterogeneity of PCNSL. Knowledge about genetic alterations in PCNSL can inform the development of novel targets for diagnosis and treatment.
Entities:
Keywords:
Diffuse large B-cell lymphoma; Gene fusions; MYD88; Next generation sequencing; Primary central nervous system lymphoma; Tumor mutation burden
Authors: Vu N Ngo; Ryan M Young; Roland Schmitz; Sameer Jhavar; Wenming Xiao; Kian-Huat Lim; Holger Kohlhammer; Weihong Xu; Yandan Yang; Hong Zhao; Arthur L Shaffer; Paul Romesser; George Wright; John Powell; Andreas Rosenwald; Hans Konrad Muller-Hermelink; German Ott; Randy D Gascoyne; Joseph M Connors; Lisa M Rimsza; Elias Campo; Elaine S Jaffe; Jan Delabie; Erlend B Smeland; Richard I Fisher; Rita M Braziel; Raymond R Tubbs; J R Cook; Denny D Weisenburger; Wing C Chan; Louis M Staudt Journal: Nature Date: 2010-12-22 Impact factor: 49.962
Authors: Aravind Subramanian; Pablo Tamayo; Vamsi K Mootha; Sayan Mukherjee; Benjamin L Ebert; Michael A Gillette; Amanda Paulovich; Scott L Pomeroy; Todd R Golub; Eric S Lander; Jill P Mesirov Journal: Proc Natl Acad Sci U S A Date: 2005-09-30 Impact factor: 11.205
Authors: Wyndham H Wilson; Ryan M Young; Roland Schmitz; Yandan Yang; Stefania Pittaluga; George Wright; Chih-Jian Lih; P Mickey Williams; Arthur L Shaffer; John Gerecitano; Sven de Vos; Andre Goy; Vaishalee P Kenkre; Paul M Barr; Kristie A Blum; Andrei Shustov; Ranjana Advani; Nathan H Fowler; Julie M Vose; Rebecca L Elstrom; Thomas M Habermann; Jacqueline C Barrientos; Jesse McGreivy; Maria Fardis; Betty Y Chang; Fong Clow; Brian Munneke; Davina Moussa; Darrin M Beaupre; Louis M Staudt Journal: Nat Med Date: 2015-07-20 Impact factor: 53.440
Authors: Jonathan E Rosenberg; Jean Hoffman-Censits; Tom Powles; Michiel S van der Heijden; Arjun V Balar; Andrea Necchi; Nancy Dawson; Peter H O'Donnell; Ani Balmanoukian; Yohann Loriot; Sandy Srinivas; Margitta M Retz; Petros Grivas; Richard W Joseph; Matthew D Galsky; Mark T Fleming; Daniel P Petrylak; Jose Luis Perez-Gracia; Howard A Burris; Daniel Castellano; Christina Canil; Joaquim Bellmunt; Dean Bajorin; Dorothee Nickles; Richard Bourgon; Garrett M Frampton; Na Cui; Sanjeev Mariathasan; Oyewale Abidoye; Gregg D Fine; Robert Dreicer Journal: Lancet Date: 2016-03-04 Impact factor: 79.321
Authors: Christine P Hans; Dennis D Weisenburger; Timothy C Greiner; Randy D Gascoyne; Jan Delabie; German Ott; H Konrad Müller-Hermelink; Elias Campo; Rita M Braziel; Elaine S Jaffe; Zenggang Pan; Pedro Farinha; Lynette M Smith; Brunangelo Falini; Alison H Banham; Andreas Rosenwald; Louis M Staudt; Joseph M Connors; James O Armitage; Wing C Chan Journal: Blood Date: 2003-09-22 Impact factor: 22.113
Authors: Jeffrey R Infante; Philippe A Cassier; John F Gerecitano; Petronella O Witteveen; Rashmi Chugh; Vincent Ribrag; Abhijit Chakraborty; Alessandro Matano; Jason R Dobson; Adam S Crystal; Sudha Parasuraman; Geoffrey I Shapiro Journal: Clin Cancer Res Date: 2016-08-19 Impact factor: 12.531
Authors: Zachary R Chalmers; Caitlin F Connelly; David Fabrizio; Laurie Gay; Siraj M Ali; Riley Ennis; Alexa Schrock; Brittany Campbell; Adam Shlien; Juliann Chmielecki; Franklin Huang; Yuting He; James Sun; Uri Tabori; Mark Kennedy; Daniel S Lieber; Steven Roels; Jared White; Geoffrey A Otto; Jeffrey S Ross; Levi Garraway; Vincent A Miller; Phillip J Stephens; Garrett M Frampton Journal: Genome Med Date: 2017-04-19 Impact factor: 11.117
Authors: Nicolai Juul Birkbak; Bose Kochupurakkal; Jose M G Izarzugaza; Aron C Eklund; Yang Li; Joyce Liu; Zoltan Szallasi; Ursula A Matulonis; Andrea L Richardson; J Dirk Iglehart; Zhigang C Wang Journal: PLoS One Date: 2013-11-12 Impact factor: 3.240
Authors: Elena N Voropaeva; Tatjana I Pospelova; Yuriy L Orlov; Maria I Churkina; Olga V Berezina; Anna A Gurazheva; Tatjana A Ageeva; Olga B Seregina; Vladimir N Maksimov Journal: Genes (Basel) Date: 2022-08-07 Impact factor: 4.141