DNA repair genes are selectively mutated in diffuse large B cell lymphomas

Miranda, Noel F C C de; Peng, Roujun; Γεωργίου, Κωνσταντίνος; Wu, Chenglin; Sorqvist, Elin Falk; Berglund, Mattias; Chen, Longyun; Gao, Zhibo; Lagerstedt, Kristina; Lisboa, Susana; Roos, Fredrik; Wezel, Tom van; Teixeira, Manuel R.; Rosenquist, Richard; Sundström, Christer; Enblad, Gunilla; Nilsson, Mats; Zeng, Yi‐Xin; Kipling, David; Pan‐Hammarström, Qiang

doi:10.1084/jem.20122842

Cited by 93 publications

(96 citation statements)

References 66 publications

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“…9,52 Notably, sample DL48, where the original PD-L1-IGH translocation was identified, carries a somatic deleterious mutation in the MSH2 gene, a major component of MMR, and shows an increased number of somatic mutations in the coding genome. 25 In addition, histologic examination confirmed CD8 1 T-cell infiltration in the sample. Taken together, a subset of DLBCLs, represented by DL48, is likely to respond well to the anti-PD-1-PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 81%

“…62 Although the mechanisms responsible for this relation are not clear, it is hypothesized that the improved responsiveness to immunotherapy is caused by an increase in the number of neoantigens as a result of the higher mutational load associated with the impaired MMR. 25,63 Aberrant SHM as well as mutations in the MMR pathway contribute to an increase of the mutation load in DLBCL. 9,52 Notably, sample DL48, where the original PD-L1-IGH translocation was identified, carries a somatic deleterious mutation in the MSH2 gene, a major component of MMR, and shows an increased number of somatic mutations in the coding genome.…”

Section: Discussionmentioning

confidence: 99%

“…24 We have previously suggested that defects in the NHEJ pathway might be associated with the formation of translocations involving the IGH locus. 25 PD-L1 and PD-L2 are signaling molecules expressed on the surface of antigen-presenting cells. 26 Upon interaction with their receptor PD-1 on effector T cells, they transmit a negative regulatory signal that leads to functional anergy of the T cells.…”

Section: Pd-l2mentioning

confidence: 99%

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Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas

Γεωργίου

Chen

Berglund

et al. 2016

Blood

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179

176

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Key Points• Translocations between PD-L1 and the IGH locus represent a genetic mechanism of PD-L1 overexpression in DLBCL.• Genetic alterations in the PD-L1/PDL-2 locus are mainly associated with the non-GCB subtype of DLBCL.Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2. Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2. Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype. (Blood. 2016;127(24):3026-3034)

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Pd-l2mentioning

confidence: 99%

See 1 more Smart Citation

Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas

Γεωργίου

Chen

Berglund

et al. 2016

Blood

Self Cite

179

176

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“…Artemis mutation combined with p53 deficiency in mice leads to development of progenitor B‐cell lymphomas with translocations in immunoglobulin genes 84, 85. In humans, Artemis mutations were recently identified in patients with diffuse large B‐cell lymphomas 86. Some studies also suggest that patients with hypomorphic Artemis mutations are predisposed to cancer, potentially due to the involvement of Artemis in DSB repair during the G2 phase of the cell cycle 87…”

Section: Mechanisms Of Cancer Developmentmentioning

confidence: 99%

Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease

Procházková

Loizou

2015

Immunology

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SummaryIn recent years, several novel congenital human disorders have been described with defects in lymphoid B‐cell and T‐cell functions that arise due to mutations in known and/or novel components of DNA repair and damage response pathways. Examples include impaired DNA double‐strand break repair, as well as compromised DNA damage‐induced signal transduction, including phosphorylation and ubiquitination. These disorders reinforce the importance of genome stability pathways in the development of lymphoid cells in humans. Furthermore, these conditions inform our knowledge of the biology of the mechanisms of genome stability and in some cases may provide potential routes to help exploit these pathways therapeutically. Here we review the mechanisms that repair programmed DNA lesions that occur during B‐cell and T‐cell development, as well as human diseases that arise through defects in these pathways.

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“…18 Dysregulation of DNA repair and damage response mechanisms involved in SHM and CSR processes are likely to play an important role in the propagation of genetic instability in DLBCL. 19 A number of studies on DLBCL, based on next-generation sequencing (NGS) approaches, have been published during recent years, 13,[20][21][22][23] uncovering novel mutation targets, further underscoring the genetic heterogeneity of this disease. Here, we present the first characterization of the coding genome of DLBCLs derived from Chinese patients.…”

Section: Introductionmentioning

confidence: 99%