LOSS OF 18Q22.1-Q23 IS SIGNIFICANTLY ASSOCIATED WITH GCB-DLBCL AND FAILURE TO ACHIEVE EFS24
Author(s): ,
Kerstin Wenzl
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
,
Michelle Manske
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
,
Keenan Hartert
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
,
Jordan Krull
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
,
Vivekananda Sarangi
Affiliations:
Department of Health Sciences Research,Mayo Clinic,Rochester,United States
,
Patricia Greipp
Affiliations:
Division of Laboratory Genetics and Genomics,Mayo Clinic,Rochester,United States
,
Matthew Maurer
Affiliations:
Health Sciences Research,Mayo Clinic,Rochester,United States
,
Andrew Feldman
Affiliations:
Division of Hematopathology,Mayo Clinic,Rochester,United States
,
Stephen Ansell
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
,
James Cerhan
Affiliations:
Department of Health Sciences Research,Mayo Clinic,Rochester,United States
Anne Novak
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
EHA Library. Wenzl K. Jun 14, 2019; 266314; PF514
Kerstin Wenzl
Kerstin Wenzl
Contributions
Abstract

Abstract: PF514

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background

Recent large next generation sequencing studies have redefined the genomic landscape of diffuse large B-cell lymphoma (DLBCL). While many of the more common genetic variants, primarily mutations, have been biologically characterized, little is known about newly emerging genetic aberrations. In particular, somatic copy number alterations remain poorly studied due to the large genomic regions they cover and the number of genes involved. This, in combination with lack of remission or early relapse in a portion of DLBCL, opens new opportunities to explore yet unidentified genetic contributions to lymphomagenesis.   

Aims

The goal of this study was to identify variants associated with failure to achieve event free survival at 24 months (EFS24) and define their biologic significance in DLBCL.

Methods

Newly diagnosed DLBCL treated with standard immunochemotherapy were included in this study (n=246). Copy number data was generated by using the molecular inversion probe OncoScan™ FFPE Assay Kit (Affymetrix, Santa Clara, CA, USA). OncoScan OSCHP files were analyzed using Nexus Copy Number 9.0 software (Biodiscovery, El Segundo, USA). Data interpretation and copy number calling was done using the human reference genome GRCh37/hg19. Files were analyzed using the Nexus FASST2-Segmentation algorithm, which is based on a Hidden Markov Model approach for calling genetic events. For functional analysis, SOCS6 was overexpressed and studied in GCB-DLBCL cell lines. 

Results

Upon review of genomic copy number data from DLBCL cases (n=246), loss of 18q22.1-q23 was a significant event in our cohort (p=0.018), is found in 11% (n=27) of DLBCL, and is enriched in germinal center DLBCL (GCB-DLBCL) patients (18/107, 17%, p<0.05) compared to activated B-cell (ABC)/non-GCB DLBCL patients (1/93, 1%).  Furthermore, GCB-DLBCL patients with a loss of 18q22.1-q23 were significantly more likely to fail EFS24 (50%, p<0.05) compared to GCB-DLBCL patients without the loss (29%).  Genes located at 18q22.1-q23 include, TMX3, DOK6 and SOCS6. SOCS family proteins have been shown to play an important role in tumor biology, although little is known about SOCS6. SOCS6 gene expression is downregulated in a variety of solid tumors and is hypermethylated in some hematological malignancies. RNASeq data from DLBCL suggest variable expression across tumors. Using a panel of GCB cell lines we found that SOCS6 expression was low to negative, and publically available cell line data suggests this region is hypermethylated. Expression of SOCS6 was higher in a panel of mantle cell lymphoma and ABC-DLBCL cell lines and this again correlated with their cell line methylation data, where no hypermethylation was found in those cell lines.  Together, this data suggests that downregulation of SOCS6 through genomic loss or hypermethylation may have biologic importance. To explore the role of SOCS6, we restored expression in GCB cell lines and immuno-fluorescence staining suggest localization to the nucleus and cytoplasm, as previously reported in other cell types.  Studies to explore the role of SOCS6 in cytokine signaling and STAT family protein regulation are ongoing.

Conclusion
Using genome copy number data from 246 DLBCL, we have found that loss of 18q22.1-q23 (p=0.018) is associated with GCB-DLBCL and failure to achieve EFS24. Furthermore, we have identified that SOCS6 may have clinical and biologic significance in GCB-DLBCL.

Session topic: 20. Lymphoma Biology & Translational Research

Keyword(s): DLBCL, Genetic, Survival

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