Genome-wide Characterization of Copy Number Variations in Diffuse Large B-cell Lymphoma with Implications in Targeted Therapy

Overview

Journal Precis Clin Med

Publisher Oxford University Press

Specialty General Medicine

Date 2022 Jun 13

PMID 35693879

Authors

Prashanthi Dharanipragada

Nita Parekh

Affiliations

Soon will be listed here.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the aggressive form of haematological malignancies with relapse/refractory in ~ 40% of cases. It mostly develops due to accumulation of various genetic and epigenetic variations that contribute to its aggressiveness. Though large-scale structural alterations have been reported in DLBCL, their functional role in pathogenesis and as potential targets for therapy is not yet well understood. In this study we performed detection and analysis of copy number variations (CNVs) in 11 human DLBCL cell lines (4 activated B-cell-like [ABC] and 7 germinal-centre B-cell-like [GCB]), that serve as model systems for DLBCL cancer cell biology. Significant heterogeneity observed in CNV profiles of these cell lines and poor prognosis associated with ABC subtype indicates the importance of individualized screening for diagnostic and prognostic targets. Functional analysis of key cancer genes exhibiting copy alterations across the cell lines revealed activation/disruption of ten potentially targetable immuno-oncogenic pathways. Genome guided therapy that putatively target these pathways is elucidated. Based on our analysis, five CNV-genes associated with worst survival prognosis are proposed as potential prognostic markers of DLBCL.

Citing Articles

An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes.

Li C, Bonder M, Syed S, Jensen M, Gerstein M, Zody M Genome Res. 2024; 34(12):2304-2318.

PMID: 39638559 PMC: 11694747. DOI: 10.1101/gr.279419.124.

Benchmarking of Approaches for Gene Copy-Number Variation Analysis and Its Utility for Genetic Aberration Detection in High-Grade Serous Ovarian Carcinomas.

Grebnev P, Meshkov I, Ershov P, Makhotenko A, Azarian V, Erokhina M Cancers (Basel). 2024; 16(19).

PMID: 39409874 PMC: 11475927. DOI: 10.3390/cancers16193252.

In Silico Identification and Functional Characterization of Genetic Variations across DLBCL Cell Lines.

Dharanipragada P, Parekh N Cells. 2023; 12(4).

PMID: 36831263 PMC: 9954129. DOI: 10.3390/cells12040596.

Spatial Heterogeneity in Large Resected Diffuse Large B-Cell Lymphoma Bulks Analysed by Massively Parallel Sequencing of Multiple Synchronous Biopsies.

Magnes T, Wagner S, Thorner A, Neureiter D, Klieser E, Rinnerthaler G Cancers (Basel). 2021; 13(4).

PMID: 33561953 PMC: 7914762. DOI: 10.3390/cancers13040650.

References

Cheng S, Yue S . Role and regulation of human tumor suppressor SUFU in Hedgehog signaling. Adv Cancer Res. 2008; 101:29-43. DOI: 10.1016/S0065-230X(08)00402-8. View

Locke F, Neelapu S, Bartlett N, Siddiqi T, Chavez J, Hosing C . Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol Ther. 2017; 25(1):285-295. PMC: 5363293. DOI: 10.1016/j.ymthe.2016.10.020. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Green D, Young H, Valencia J . Current prospects of type II interferon γ signaling and autoimmunity. J Biol Chem. 2017; 292(34):13925-13933. PMC: 5572907. DOI: 10.1074/jbc.R116.774745. View

Dharanipragada P, Vogeti S, Parekh N . iCopyDAV: Integrated platform for copy number variations-Detection, annotation and visualization. PLoS One. 2018; 13(4):e0195334. PMC: 5886540. DOI: 10.1371/journal.pone.0195334. View

Scott D . Cell-of-Origin in Diffuse Large B-Cell Lymphoma: Are the Assays Ready for the Clinic?. Am Soc Clin Oncol Educ Book. 2015; :e458-66. DOI: 10.14694/EdBook_AM.2015.35.e458. View

Gao J, Aksoy B, Dogrusoz U, Dresdner G, Gross B, Sumer S . Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013; 6(269):pl1. PMC: 4160307. DOI: 10.1126/scisignal.2004088. View

Szklarczyk D, Morris J, Cook H, Kuhn M, Wyder S, Simonovic M . The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2016; 45(D1):D362-D368. PMC: 5210637. DOI: 10.1093/nar/gkw937. View

Cardenas M, Oswald E, Yu W, Xue F, MacKerell Jr A, Melnick A . The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target. Clin Cancer Res. 2016; 23(4):885-893. PMC: 5315622. DOI: 10.1158/1078-0432.CCR-16-2071. View

10.

Chapuy B, Stewart C, Dunford A, Kim J, Kamburov A, Redd R . Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018; 24(5):679-690. PMC: 6613387. DOI: 10.1038/s41591-018-0016-8. View

11.

Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula S, Shen Q . Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell. 2005; 7(5):445-55. DOI: 10.1016/j.ccr.2005.03.037. View

12.

Harada T, Chelala C, Crnogorac-Jurcevic T, Lemoine N . Genome-wide analysis of pancreatic cancer using microarray-based techniques. Pancreatology. 2008; 9(1-2):13-24. DOI: 10.1159/000178871. View

13.

Dal Bo M, Bomben R, Hernandez L, Gattei V . The MYC/miR-17-92 axis in lymphoproliferative disorders: A common pathway with therapeutic potential. Oncotarget. 2015; 6(23):19381-92. PMC: 4637292. DOI: 10.18632/oncotarget.4574. View

14.

Petrich A, Leshchenko V, Kuo P, Xia B, Thirukonda V, Ulahannan N . Akt inhibitors MK-2206 and nelfinavir overcome mTOR inhibitor resistance in diffuse large B-cell lymphoma. Clin Cancer Res. 2012; 18(9):2534-44. PMC: 3889476. DOI: 10.1158/1078-0432.CCR-11-1407. View

15.

Song M, Park B, Uhm J . Understanding Immune Evasion and Therapeutic Targeting Associated with PD-1/PD-L1 Pathway in Diffuse Large B-cell Lymphoma. Int J Mol Sci. 2019; 20(6). PMC: 6470519. DOI: 10.3390/ijms20061326. View

16.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

17.

Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V . Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood. 2005; 106(9):3183-90. PMC: 1895326. DOI: 10.1182/blood-2005-04-1399. View

18.

Riley J . PD-1 signaling in primary T cells. Immunol Rev. 2009; 229(1):114-25. PMC: 3424066. DOI: 10.1111/j.1600-065X.2009.00767.x. View

19.

Morin R, Mendez-Lago M, Mungall A, Goya R, Mungall K, Corbett R . Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476(7360):298-303. PMC: 3210554. DOI: 10.1038/nature10351. View

20.

Patel R, Jain M . NGS QC Toolkit: a toolkit for quality control of next generation sequencing data. PLoS One. 2012; 7(2):e30619. PMC: 3270013. DOI: 10.1371/journal.pone.0030619. View