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Relapsed diffuse large B-cell lymphoma present different genomic patterns of alterations between early and late relapses

ABSTRACT: Despite major advances in first-line treatment, a significant proportion of patients with diffuse large B-cell lymphoma (DLBCL) will experience treatment failure. Time of relapse is a major prognostic parameter in this context, with a particularly poor prognosis for early relapse. Our purpose was to determine genomic alterations associated with early-relapsed (ER) and late-relapsed (LR) DLBCLs, using high resolution array-based comparative genomic hybridization and integrating structural abnormalities and gene expression of 39 samples from the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study. ER and LR DLBCLs present a similar landscape of large copy number variations (CNVs), with an average 14.89 and 16.11 CNVs per sample, respectively (p=0.81). 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, genetic abnormalities were related to regulation of transcription, cell cycle and apoptosis, with duplications of histone H1T (31%), deletions of DIABLO (26%), PTMS (21%) and CK2B (15%). In LR DLBCLs, genetic aberrations were related to immune response, with alterations of IgHV (40%), IgKV (15%), and deletions of B2M (20%) and CD58 (10%), regulation of cell proliferation, with duplications of HES1 and DVL3 (25% and 20%, respectively) and regulation of transcription, with MTERF4 deletions (20%). This study provides new insights into the genetic abnormalities in relapsed DLBCLs. Dysregulation of cell cycle, apoptosis and gene transcription may indicate targeted therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73791 | GEO | 2016/09/26

SECONDARY ACCESSION(S): PRJNA297892

REPOSITORIES: GEO

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Project description:Objective: Chromosomal 1q21.1 deletions and duplications are genomic disorders which are usually diagnosed postnatally. However, the genotype-phenotype correlations of 1q21.1 copy number variants (CNVs) during prenatal period are still not clear. This study aimed to provide a systematical summary of prenatal phenotypes for such genomic disorders. Methods: Twenty-six prenatal amniotic fluid samples diagnosed with 1q21.1 microdeletions/microduplications were obtained from pregnant women who opted for invasive prenatal testing. Karyotypic analysis and chromosomal microarray analysis (CMA) were performed for all cases simultaneously. The pregnancy outcomes and health conditions after birth for all cases were followed up. Meanwhile, prenatal cases with 1q21.1 microdeletions or microduplications in the literature were retrospectively collected. Results: Eleven pregnancies (11/8252, 0.13%) with 1q21.1 microdeletions and fifteen (15/8252, 0.18%) with 1q21.1 microduplications were identified. Among these 1q21.1 CNVs, four cases covered thrombocytopenia-absent radius (TAR) region, sixteen cases covered 1q21.1 recurrent microdeletion/microduplication region, and six cases covered all regions mentioned above. The prenatal abnormal ultrasound findings were recorded in four participants with 1q21.1 deletions and seven participants with 1q21.1 duplications. Finally, three cases with 1q21.1 deletions and five with 1q21.1 duplications terminated their pregnancies. Conclusion: 1q21.1 microdeletions were associated with increased nuchal translucency (NT), anomalies of urinary system and cardiovascular abnormalities, and 1q21.1 microduplications were correlated with cardiovascular malformations, nasal bone dysplasia and increased NT in prenatal setting. In addition, cerebral ventriculomegaly might be correlated with 1q21.1 microduplications. Considering the variable expressivity and incomplete penetrance of 1q21.1 CNVs, long term follow up after birth should be carried out for these cases. We identified 26 fetuses carrying the 1q21.1 microdeletions and microduplications using chromosomal microarray analysis. And diverse prenatal phenotypes and the critical genes involved in the deleted/duplicated regions were described in this study.

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Relapsed diffuse large B-cell lymphoma present different genomic patterns of alterations between early and late relapses

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