title: Clinicopathological characteristics and genomic profile of primary sinonasal tract diffuse large B cell lymphoma (DLBCL) reveals gain at 1q31 and RGS1 encoding protein; high RGS1 immunohistochemical expression associates with poor overall survival in DLBCL not otherwise specified (NOS).
abstract: OBJECTIVE
  We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B cell lymphoma (DLBCLsn) in a series of 240 cases of DLBCL not otherwise specified [DLBCLall (NOS)], including DLBCLsntraining set (n = 11) and validation set (n = 18), and DLBCLnon-sn(n = 211).
  
  
  RESULTS
  In the training set, 82% had a non-germinal center B-cell-like (Hans' Classifier) (non-GCB) phenotype and 18% were Epstein-Barr virus-encoded small RNAs (EBER)+. The genomic profile showed gains(+)of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-)of 6q26q27 (55%) and 9p21.3 (64%); and copy number neutral loss of heterozygosity (LOH) (acquired uniparental disomy, UPD) at 6p25.3p21.31 (36%). This profile is comparable to DLBCLNOS(GSE11318, n = 203.) and closer to non-GCB/activated B-cell-like subtype (ABC). Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCLsn(P < 0.001). Array results were verified successfully by fluorescence in situ hybridization (FISH) on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), -9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82-91% agreement. Minimal common regions included biologically relevant genes of MNDA (+1q23.1), RGS1 and RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 (BLIMP1) and PARK2 (-6q21q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1) and BCL2 (+18q21.33). Correlation between DNA copy number and protein immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-like tumour associated macrophages (TAMs) and CD8+T lymphocytes that associated with higher genomic instability. The DLBCLsnvalidation set confirmed the clinicopathological characteristics, all FISH loci and immunohistochemistry (IHC) for RGS1. RGS1, one of the most frequently altered genes, was analysed by IHC in DLBCLalland high RGS1 expression associated with non-GCB, EBER+and unfavourable overall survival (hazard ratio = 1.794; P = 0.016).
  
  
  CONCLUSIONS
  DLBCLsnhas a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCLall (NOS).
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Joaquim
authors: J
authors: Carreras
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Yara Y
authors: YY
authors: Kikuti
authors: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors: Sílvia
authors: S
authors: Beà
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Masashi
authors: M
authors: Miyaoka
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Shinichiro
authors: S
authors: Hiraiwa
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Haruka
authors: H
authors: Ikoma
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Ryoko
authors: R
authors: Nagao
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Sakura
authors: S
authors: Tomita
authors: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors: David
authors: D
authors: Martin-Garcia
authors: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors: Itziar
authors: I
authors: Salaverria
authors: Department of Hematology and Oncology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Ai
authors: A
authors: Sato
authors: Department of Hematology and Oncology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Akifumi
authors: A
authors: Ichiki
authors: Monoclonal Antibodies Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors: Giovanna
authors: G
authors: Roncador
authors: Department of Pathology, MD Anderson Cancer Center Madrid, Madrid, Spain.
authors: Juan F
authors: JF
authors: Garcia
authors: Department of Hematology and Oncology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Kiyoshi
authors: K
authors: Ando
authors: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors: Elias
authors: E
authors: Campo
authors: Department of Pathology, Tokai University, School of Medicine, Kanagawa, Japan.
authors: Naoya
authors: N
authors: Nakamura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020710:RGS Proteins / Q000235:genetics*; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D020710:RGS Proteins; C080831:RGS1 protein, human
keywords: DNA copy number changes; FISH technique; RGS1; digital image quantification; immunohistochemistry; prognosis; sinonasal diffuse large B cell lymphoma (DLBCL); tumour microenvironment