Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

Morin, Ryan D.; Méndez-Lago, María; Mungall, Andrew J.; Goya, Rodrigo; Mungall, Karen; Corbett, Richard; Johnson, Nathalie A.; Severson, Tesa; Chiu, Readman; Field, Matthew A.; Jackman, Shaun D.; Krzywinski, Martin; Scott, David W.; Trinh, Diane L.; Tamura-Wells, Jessica; Li, Sa; Firme, Marlo; Rogić, Sanja; Griffith, Malachi; Chan, Susanna; Yakovenko, Oleksandr; Meyer, Irmtraud M.; Zhao, Eric Y.; Smailus, Duane E.; Moksa, Michelle; Chittaranjan, Suganthi; Rimsza, Lisa M.; Brooks‐Wilson, Angela; Spinelli, John J.; Ben-Neriah, Susana; Meissner, Barbara; Woolcock, Bruce W.; Boyle, Merrill; McDonald, Helen; Tam, Angela; Zhao, Yongjun; Delaney, Allen; Zeng, Thomas; Tse, Kane; Butterfield, Yaron S.N.; Birol, İnanç; Holt, Robert A.; Schein, Jacqueline E.; Horsman, Douglas E.; Moore, Richard A.; Jones, Steven J.M.; Connors, Joseph M.; Hirst, Martin; Gascoyne, Randy D.; Marra, Marco A.

doi:10.1038/nature10351

Cited by 1,468 publications

(1,520 citation statements)

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“…Since somatic CREBBP mutation is a very frequent early event in follicular B‐cell lymphoma and diffuse large B‐cell lymphoma (Lohr et al, 2012; Morin et al, 2011; Pasqualucci et al, 2011; Zhang et al, 2011), this case was studied for somatic CREBBP alterations (Stevens et al, 2017). A somatic CREBBP mutation on one allele was found (His1438Asp, variant allele frequency [VAF] 25%), while the known germline mutation ( CREBBP c.4837delG) was found in only 6% of sequence reads.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in CREBBP and EP300 have been demonstrated in various benign and malignant tumors, including in up to 40% of diffuse large cell B‐cell lymphoma (DLBCL) and follicular lymphoma cases (Lohr et al, 2012; Morin et al, 2011; Pasqualucci et al, 2011; Zhang et al, 2011). A specific type of acute myeloid leukemia is associated with a chromosomal translocation involving CREBBP (Rozman et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Benign and malignant tumors in Rubinstein–Taybi syndrome

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Belzen

Overbeek

et al. 2018

American J of Med Genetics Pt A

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Rubinstein–Taybi syndrome (RSTS) is a multiple congenital anomalies syndrome associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of specific benign and possibly also malignant tumors. We identified all known individuals diagnosed with RSTS in the Netherlands until 2015 (n = 87) and studied the incidence and character of neoplastic tumors in relation to their CREBBP/EP300 alterations. The population–based Dutch RSTS data are compared to similar data of the Dutch general population and to an overview of case reports and series of all RSTS individuals with tumors reported in the literature to date. Using the Nationwide Network and Registry of Histopathology and Cytopathology in the Netherlands (PALGA Foundation), 35 benign and malignant tumors were observed in 26/87 individuals. Meningiomas and pilomatricomas were the most frequent benign tumors and their incidence was significantly elevated in comparison to the general Dutch population. Five malignant tumors were observed in four persons with RSTS (medulloblastoma; diffuse large‐cell B‐cell lymphoma; breast cancer; non‐small cell lung carcinoma; colon carcinoma). No clear genotype–phenotype correlation became evident. The Dutch population‐based data and reported case studies underscore the increased incidence of meningiomas and pilomatricomas in individuals with RSTS. There is no supporting evidence for an increased risk for malignant tumors in individuals with RSTS, however, due to the small numbers this risk may not be fully dismissed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Benign and malignant tumors in Rubinstein–Taybi syndrome

Boot

Belzen

Overbeek

et al. 2018

American J of Med Genetics Pt A

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“…19 Briefly, paired end reads, obtained by sequencing both ends of each DNA fragment of an RNA-seq library, were aligned to the human reference genome (hg18) and exon junction sequences (to allow correct alignment of reads spanning exons) using the Burrows-Wheeler Aligner. 25 Single nucleotide variants were identified with SNVMix software (http://compbio.bccrc.ca/software/snvmix/).…”

Section: Cytogenetic Analysismentioning

confidence: 99%

“…16 Using the transcriptome sequencing method RNA-seq 17 in 89 DLBCL samples, we recently identified genomic changes that drive the pathogenesis of adult DLBCL. 18,19 The most commonly mutated gene, mutated in 33/89 transcriptomes (37%) was BCL2. 19 The aims of the current study were to determine the frequency and distribution of BCL2 mutations in DLBCL in a large number of cases, assess the relationship between gene mutation and BCL2 protein expression or BCL2 translocation, and determine the impact of mutations on immunohistochemical detection of protein expression and clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

“…18,19 The most commonly mutated gene, mutated in 33/89 transcriptomes (37%) was BCL2. 19 The aims of the current study were to determine the frequency and distribution of BCL2 mutations in DLBCL in a large number of cases, assess the relationship between gene mutation and BCL2 protein expression or BCL2 translocation, and determine the impact of mutations on immunohistochemical detection of protein expression and clinical outcome. We also tested whether BCL2 mutations are specific to DLBCL by sequencing the BCL2 gene in other lymphoma subtypes with and without BCL2 translocations.…”

Section: Introductionmentioning

confidence: 99%

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BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

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BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-kB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.Leukemia ( BCL2, discovered because of its involvement in t(14;18) in follicular lymphoma (FL), 3 has a central role in the inhibition of apoptosis. 4 BCL2 is normally transiently expressed during B-cell maturation. The t(14;18) translocation causes constitutive overexpression of BCL2 by juxtaposing it to immunoglobulin heavy chain gene enhancer elements. This translocation is found in B20% of DLBCL, 5 most often in the GCB subtype of DLBCL. 6 Other mechanisms of BCL2 deregulation, more often observed in ABC DLBCLs, include amplification of the BCL2 gene or its transcriptional upregulation through constitutive activation of the nuclear factor-kB pathway. 7 Saito et al. 8 reported that the BCL2 promoter can also be aberrantly hypermutated in DLBCL, which may prevent its inhibition by MIZ1 and BCL6. 8 They found a high number of mutations in BCL2 and suggested that the mutations described were the result of somatic hypermutation (SHM). Mutations in BCL2 have been shown to cause false-negative protein expression results in immunohistochemistry assays in FL; 9,10 however, no large study has so far investigated whether this occurs in DLBCL.

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Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity

et al. 2022

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Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.

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Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

Cited by 1,468 publications

References 50 publications

Benign and malignant tumors in Rubinstein–Taybi syndrome

Benign and malignant tumors in Rubinstein–Taybi syndrome

BCL2 mutations in diffuse large B-cell lymphoma

Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity

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