Relapsed diffuse large B-cell lymphoma present different genomic profiles between early and late relapses.
Despite major advances in first-line treatment, a significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will experience treatment failure. Prognosis is particularly poor for relapses occurring less than one year after the end of first-line treatment (early relapses/ER) compared to those occurring more than one year after (late relapses/LR). To better understand genomic alterations underlying the delay of relapse, we identified copy number variations (CNVs) on 39 tumor samples from a homogeneous series of patients included in the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) prospective study. To identify CNVs associated with ER or LR, we devised an original method based on Significance Analysis of Microarrays, a permutation-based method which allows control of false positives due to multiple testing. Deletions of CDKN2A/B (28%) and IBTK (23%) were frequent events in relapsed DLBCLs. We identified 56 protein-coding genes and 25 long non-coding RNAs with significantly differential CNVs distribution between ER and LR DLBCLs, with a false discovery rate < 0.05. In ER DLBCLs, CNVs were related to transcription regulation, cell cycle and apoptosis, with duplications of histone H1T (31%), deletions of DIABLO (26%), PTMS (21%) and CK2B (15%). In LR DLBCLs, CNVs were related to immune response, with deletions of B2M (20%) and CD58 (10%), cell proliferation regulation, with duplications of HES1 (25%) and DVL3 (20%), and transcription regulation, with MTERF4 deletions (20%). This study provides new insights into the genetic aberrations in relapsed DLBCLs and suggest pathway-targeted therapies in ER and LR DLBCLs.
Inserm U954, Faculty of Medicine, Nancy, France.|Hematology, Laboratory Department, University Hospital of Nancy, Nancy, France.
Julien
J
Broséus
ZhongNan Hospital of Wuhan University, Wuhan, China.
Gaili
G
Chen
Inserm U954, Faculty of Medicine, Nancy, France.
Sébastien
S
Hergalant
LINA DUKe, UMR 6241, Université de Nantes, Nantes, France.
Gérard
G
Ramstein
Hemato-oncology, University Hospital of l'Archet, Nice, France.
Nicolas
N
Mounier
Inserm U954, Faculty of Medicine, Nancy, France.|Biochemistry, Laboratory Department, University Hospital of Nancy, Nancy, France.
Jean-Louis
JL
Guéant
Inserm U954, Faculty of Medicine, Nancy, France.|Hematology Department, University Hospital of Nancy, Nancy, France.
Pierre
P
Feugier
APHP, Saint-Louis Hospital, Hemato-Oncology Department, Paris, France.
Christian
C
Gisselbrecht
APHP, Saint-Louis Hospital, Hemato-Oncology Department, Paris, France.|Paris Diderot University-Sorbonne Paris-Cité, Paris, France.
Catherine
C
Thieblemont
Inserm U954, Faculty of Medicine, Nancy, France.|DRCI, University Hospital of Nancy, Nancy, France.
Rémi
R
Houlgatte
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D059467:Transcriptome; D017211:Treatment Failure; D055815:Young Adult
D014408:Biomarkers, Tumor
copy number variations; diffuse large B-cell lymphoma; early relapse; genomics; late relapse