High‐throughput sequencing analysis of the chromosome 7q32 deletion reveals <scp>IRF</scp>5 as a potential tumour suppressor in splenic marginal‐zone lymphoma

Fresquet, Vicente; Robles, Eloy F.; Parker, Antón; Martínez‐Useros, Javier; Mena, Moreno; Malumbres, Raquel; Agirre, Xabier; Catarino, Susana Oliveira; Arteta, David; Osaba, Lourdes; Mollejo, Manuela; Hernández-Rivas, Jesús María; Calasanz, Marı́a José; Daibata, Masanori; Dyer, Martin J. S.; Prósper, Felipe; Vizcarra, E; Piris, Miguel Á.; Oscier, David; Martínez-Climent, José A.

doi:10.1111/j.1365-2141.2012.09226.x

Cited by 45 publications

(36 citation statements)

References 47 publications

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“…In doing so, we found CUL1 , FLNC and EZH2 mutations in individual cases (Table 2 ). Of these gene mutations, only FLNC was located within the published 7q MDR [3,20]. FLNC mutations have not been previously identified in a series eight del(7q) cases [20], suggesting that the prevalence of FLNC mutation is low in this sub-type of SMZL.…”

Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing Identifies Novel Recurrently Mutated Genes in Patients with Splenic Marginal Zone Lymphoma

et al. 2013

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The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.

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Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing Identifies Novel Recurrently Mutated Genes in Patients with Splenic Marginal Zone Lymphoma

et al. 2013

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“…Moreover, deletions of chromosome 7q32 are associated with downregulation of IRF5 function, disease progression, and poor prognosis in patients with marginal zone lymphoma. Genetic polymorphisms of IRF5 may serve as biomarkers to predict clinical responses to immunotherapy and chemotherapy in patients with melanoma and hematologic malignancies, respectively (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

et al. 2014

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Resistance to anticancer therapeutics greatly affects the phenotypic and functional properties of tumor cells, but how chemoresistance contributes to the tumorigenic activities of cancer stem-like cells remains unclear. In this study, we found that a characteristic of cancer stem-like cells from chemoresistant tumors (CSC-R) is the ability to produce a variety of proinflammatory cytokines and to generate M2-like immunoregulatory myeloid cells from CD14 þ monocytes. Furthermore, we identified the IFN-regulated transcription factor IRF5 as a CSC-Rspecific factor critical for promoting M-CSF production and generating tumorigenic myeloid cells. Importantly, myeloid cells primed with IRF5 þ CSC-R facilitate the tumorigenic and stem cell activities of bulk tumors.Importantly, the activation of IRF5/M-CSF pathways in tumor cells were correlated with the number of tumorassociated CSF1 receptor þ M2 macrophages in patients with non-small lung cancer. Collectively, our findings show how chemoresistance affects the properties of CSCs in their niche microenvironments. Cancer Res; 74(10); 2698-709. Ó2014 AACR.

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“…Copy number alterations (CNA) data were obtained from our previous publications on genome-wide DNA profiling. 2,4,17 Mutation status and familyusage of immunoglobulin variable heavy-chain (IGHV) genes were derived from previous studies.…”

Section: Genome-wide Promoter-methylation Profilingmentioning

confidence: 99%

DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

Arribas

Rinaldi

Mensah

et al. 2015

Blood

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Key Points• Methylation profiling identifies subgroups of SMZL with distinct biological features.• Demethylating agents can reverse some of the adverse epigenetic alterations.Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation. (Blood. 2015;125(12):1922-1931

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High‐throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal‐zone lymphoma

Cited by 45 publications

References 47 publications

Whole Exome Sequencing Identifies Novel Recurrently Mutated Genes in Patients with Splenic Marginal Zone Lymphoma

Whole Exome Sequencing Identifies Novel Recurrently Mutated Genes in Patients with Splenic Marginal Zone Lymphoma

Cancer Stem-like Cells Derived from Chemoresistant Tumors Have a Unique Capacity to Prime Tumorigenic Myeloid Cells

DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

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