CREBBP gene mutations are frequently detected in in situ follicular neoplasia

Schmidt, Janine; Ramis-Zaldívar, Joan Enric; Bonzheim, Irina; Steinhilber, Julia; Müller, Inga; Haake, Andrea; Yu, Shan; Fend, Falko; Salaverría, Itziar; Siebert, Reiner; Jaffe, Elaine S.; Quintanilla-Martı́nez, Leticia

doi:10.1182/blood-2018-03-837039

Cited by 37 publications

(46 citation statements)

References 25 publications

(34 reference statements)

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“…Mutations in the Creb-binding protein gene (CREBBP) are associated with follicular neoplasia and lymphoblastic leukaemia [39,40] and occasional focal losses and point mutations of the CREBBP gene have been recorded in retinoblastoma tumours [19,20]. We recorded two tumours with mutations in CREBBP.…”

Section: Other Potential Driver Mutations Identified In Retinoblastommentioning

confidence: 99%

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

Davies

Broad

Onadim

et al. 2021

Cancers

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The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.

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Section: Other Potential Driver Mutations Identified In Retinoblastommentioning

confidence: 99%

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

Davies

Broad

Onadim

et al. 2021

Cancers

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“…These mutations are acquired at an early stage of FL development by a common ancestral clone that subsequently progresses to FL or tFL through divergent evolution (Green et al, 2015;Okosun et al, 2014;Pasqualucci et al, 2014). Accordingly, CREBBP-mutated B cells have been found in a pre-malignant condition known as FL in situ, often together with the hallmark t(14;18) translocation deregulating BCL2 (Schmidt et al, 2018). Mutations in CREBBP are mono-allelic in 80% of DLBCL and over 50% of FL cases, leaving the residual wild-type (WT) allele expressed (García-Ramírez et al, 2017;Pasqualucci et al, 2011a).…”

Section: Introductionmentioning

confidence: 99%

Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma

et al. 2019

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Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.

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“…Since BCL2-IGH occurs very early in the development of FL during the V(D)J recombination ( 12 ), complete loss of function of CREBBP due to combined CIITA-CREBBP fusion and mutation is most likely an early but secondary event as well-demonstrated by Horton et al ( 13 ). CREBBP mutations occur in ~64% of FL, and were proposed to serve as early driver mutations ( 13 , 14 ). Although it is a well-known phenomenon that radiation alone or in combination with chemotherapy increases the likelihood of secondary translocations and/or mutations ( 15 ), based on the early studies in particular CREBBP mutations were frequently detected in in situ follicular neoplasm ( 13 , 14 ), the CREBBP mutation and translocation (CIITA-CREBBP) were most likely de novo rather than therapy-induced secondary events because of the additional facts that the patient had never received radiation therapy, and this biopsy were performed only after the first cycle of R-CHOP chemotherapy, too soon interval to evoke such genetic event.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Multiple Chromosomal Translocations Including Novel CIITA-CREBBP Fusion and Mutations in a Follicular Lymphoma

Wang

Sokol²,

Goodman

et al. 2021

Front. Oncol.

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The pathogenesis of follicular lymphoma is a multi-step process, in which chromosomal translocation between immunoglobulin heavy chain (IgH) and anti-apoptotic B-cell lymphoma 2 (BCL2), namely IgH-BCL2, is an earliest step, followed by other genetic/genomic alterations including but not limited to mutation of CREB binding protein (CREBBP). MHC class II transactivator (CIITA) is a transcription regulator responsible for expression of MHC class II molecules including HLA-DR in human. We report herein a novel fusion gene involving CIITA and CREBBP in a patient with a low-grade follicular lymphoma (FL) but with high Ki-67 proliferation index. In addition, our patient also harbors CREBBP mutation. Together, we postulate that total loss of CREBBP function may contribute, in part, to the lymphoma genesis. Furthermore, this patient has addition rare (TBL1XR1-TP63) and common (IgH-BCL2) chromosomal translocations and multiple mutations including BCL2, BRAF, MUTYH, and STAT6.

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CREBBP gene mutations are frequently detected in in situ follicular neoplasia

Cited by 37 publications

References 25 publications

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

Whole-Genome Sequencing of Retinoblastoma Reveals the Diversity of Rearrangements Disrupting RB1 and Uncovers a Treatment-Related Mutational Signature

Unique and Shared Epigenetic Programs of the CREBBP and EP300 Acetyltransferases in Germinal Center B Cells Reveal Targetable Dependencies in Lymphoma

Case Report: Multiple Chromosomal Translocations Including Novel CIITA-CREBBP Fusion and Mutations in a Follicular Lymphoma

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