Genetic landscape of hepatitis B virus–associated diffuse large B-cell lymphoma

Ren, Weicheng; Ye, Xiaofei; Su, Hong; Li, Wei; Liu, Dongbing; Pirmoradian, Mohammad; Li, Linyu; Zhang, Bo; Zhang, Qiang; Chen, Longyun; Nie, Man; Liu, Yao; Meng, Bin; Huang, Huiqiang; Jiang, Wenqi; Zeng, Yi‐Xin; Li, Wenyu; Wu, Kui; Hou, Yong; Wiman, Klas G.; Li, Zhiming; Zhang, Huilai; Peng, Roujun; Zhu, Shida; Pan‐Hammarström, Qiang

doi:10.1182/blood-2017-11-817601

Cited by 87 publications

(141 citation statements)

References 65 publications

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“…The genetic features of the RC-K8 cell line showed some similarity to the BN2 (based on BCL6 fusions and NOTCH1 CNV changes) (4) or the C1 (based on BCL6 structural variants and mutations of NOTCH signaling pathway components) molecular subtype (3), but also have distinct genetic features. We furthermore noted that it resembled what we have discovered previously in DLBCL samples associated with HBV infection (5), with translocations in BCL6, copy number changes in NOTCH1 and CD70, as well as mutations in ZFP36L1, SGK1, IKZF3, TP63 and TP73. It has been shown that the HBV protein HBx can directly interact with CREBBP/EP300 and facilitate the recruitment of the complex onto CREB-responsive promoters, upregulating downstream oncogenes (40).…”

Section: Discussionsupporting

confidence: 84%

“…By re-analyzing a Chinese DLBCL cohort (5), we observed that mutations were more frequently identified in CREBBP than that in EP300 (11.7% vs. 3.3% of 275 samples, Figure 2A, Table S5), which is in agreement with previous studies (12,36). Notably, over 70% of these mutations affected the HAT-domain (Figure 2A).…”

Section: Dlbcl Cells With Either Ep300 or Crebbp Mutations Are Sensitsupporting

confidence: 90%

“…This was supported by the observation that the CREBBP-targeted genes were significantly upregulated in HBsAg + tumors compared to HBsAgtumors ( Figure S8). Targeting the HAT-functions of CREBBP/EP300 can thus be a new direction in developing effective treatment for HBV-associated DLBCL patients, who usually have a poor response to the current therapy (5).…”

Section: Discussionmentioning

confidence: 99%

“…The ABC subtype and selected molecular subtypes (C3 and C5 in Chapuy et al (3); MCD and N1 in Schmitz et al (4)) are associated with a poor prognosis. Recently, we have shown that hepatitis B virus (HBV)-related DLBCLs are associated with unique genetic and clinical features as well as a shorter overall patient survival, and may be considered as a distinct subtype (5). DLBCL is thus a highly heterogeneous disease, and identification of genetic vulnerabilities that are specific to a subtype or subgroup of patients will aid the development of novel targeted therapeutic strategies and improve clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

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Essentiality ofCREBBPinEP300truncated B-cell lymphoma revealed by genome-wide CRISPR-Cas9 screen

Nie

Zhang

et al. 2019

Preprint

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Histone acetyltransferases (HATs), including CREBBP and EP300, are frequently mutated in B-cell malignancies and usually play a tumor-suppressive role. In this study, we performed whole genome and transcriptome sequencing and a genome-wide CRISPR-Cas9 knockout screen to study a germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell line (RC-K8). Using a summarizing method that is optimized to address the complexity introduced by the time-course design, we identified a distinct pattern of genetic essentialities in RC-K8, including a dependency on CREBBP and MDM2, shown already at early time points and a gradually increased dependency on oxidative phosphorylation related genes. The dependency on CREBBP is associated with the corresponding genetic alterations identified in this cell line, i.e. a balanced translocation involves EP300, which resulted in a truncated form of protein that lacks the critical bromodomain and HAT domain. We further evaluated the previously published CRISPR-Cas9 screens and identified a genetic essentiality of CREBBP or EP300 gene in a small set of cancer cell lines, including several DLBCL cell lines that are highly sensitive for EP300 knockout and with CREBBP mutations or copy number loss. The dependency of the remaining HAT function in CREBBP and/or EP300-deficient genotype was validated by testing the HAT-domain inhibitor A-485. Our study suggests that integration of the unbiased, time-course-based functional screen results with the genomic and transcriptomic data can identify druggable vulnerability in individual or subgroups of cell lines/patients, which may help to develop more effective therapeutic strategies for cancers that are genetically highly heterogeneous, like DLBCL.

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Section: Discussionsupporting

confidence: 84%

Section: Dlbcl Cells With Either Ep300 or Crebbp Mutations Are Sensitsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Essentiality ofCREBBPinEP300truncated B-cell lymphoma revealed by genome-wide CRISPR-Cas9 screen

Nie

Zhang

et al. 2019

Preprint

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“…The resulting list was not satisfactory as it lacked important known patterns; for instance signature 3, associated with homologous recombination repair deficiency was not found to be active in any tumor of the prostate cohort, while signature 3 in prostate cancer is well described in the literature [2, 19, 38]. We therefore completed the signatures present in each cancer type based on the literature [2, 39, 20, 40, 41, 42, 21, 43, 19, 44, 26, 45, 46], and used the resulting matrix in all CloneSig runs on the TCGA. Our curated list of signatures present in each cancer type is provided in Table S4.…”

Section: Methodsmentioning

confidence: 99%

CloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data

Abecassis

Reyal

Vert

2019

Preprint

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The possibility to sequence DNA in cancer samples has triggered much effort recently to identify the forces at the genomic level that shape tumorigenesis and cancer progression. It has resulted in novel understanding or clarification of two important aspects of cancer genomics: (i) intra-tumor heterogeneity (ITH), as captured by the variability in observed prevalences of somatic mutations within a tumor, and (ii) mutational processes, as revealed by the distribution of the types of somatic mutation and their immediate nucleotide context. These two aspects are not independent from each other, as different mutational processes can be involved in different subclones, but current computational approaches to study them largely ignore this dependency. In particular, sequential methods that first estimate subclones and then analyze the mutational processes active in each clone can easily miss changes in mutational processes if the clonal decomposition step fails, and conversely information regarding mutational signatures is overlooked during the subclonal reconstruction. To address current limitations, we present CloneSig, a new computational method to jointly infer ITH and mutational processes in a tumor from bulk-sequencing data, including whole-exome sequencing (WES) data, by leveraging their dependency. We show through an extensive benchmark on simulated samples that CloneSig is always as good as or better than state-of-the-art methods for ITH inference and detection of mutational processes. We then apply CloneSig to a large cohort of 8,954 tumors with WES data from the cancer genome atlas (TCGA), where we obtain results coherent with previous studies on whole-genome sequencing (WGS) data, as well as new promising findings. This validates the applicability of CloneSig to WES data, paving the way to its use in a clinical setting where WES is increasingly deployed nowadays.

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The dual role of CD70 in B‐cell lymphomagenesis

Nie

Ren

et al. 2022

Clinical & Translational Med

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Background CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B‐cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD‐L1 inhibitor in a murine lymphoma model. Results We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over‐expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8 + T cells were furthermore identified in CD70 high‐expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD‐L1 interactions could reduce CD70 + lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. Conclusions Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno‐therapeutic strategies.

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Genetic landscape of hepatitis B virus–associated diffuse large B-cell lymphoma

Cited by 87 publications

References 65 publications

Essentiality ofCREBBPinEP300truncated B-cell lymphoma revealed by genome-wide CRISPR-Cas9 screen

Essentiality ofCREBBPinEP300truncated B-cell lymphoma revealed by genome-wide CRISPR-Cas9 screen

CloneSig can jointly infer intra-tumor heterogeneity and mutational signature activity in bulk tumor sequencing data

The dual role of CD70 in B‐cell lymphomagenesis

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