High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations

Pillonel, Vincent; Juškevičius, Darius; Ng, Charlotte K.Y.; Bodmer, Andrea; Zettl, Andreas; Jucker, David; Dirnhofer, Stephan; Tzankov, Alexandar

doi:10.1038/s41375-018-0082-4

Cited by 58 publications

(68 citation statements)

References 75 publications

(99 reference statements)

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“…Recurrently detected copy number variants and mutations found in diffuse follicular lymphoma (dFL) compared to previously published studies of conventional follicular lymphoma (cFL) and marginal zone lymphoma (MZL). CNVs in dFL detected in the present report and previously published studies* (3,20) were grouped and compared to previously published studies of cFL (4-10) and MZL (26,29,(38)(39)(40)(41). Mutations in dFL detected in the present report and previously published studies* (20,21) were grouped and compared to mutations found in previously published studies of cFL (11)(12)(13)(14)(15)(16)(17)(18)(19) and MZL (26,(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Our Data Demonstrated New Associations Of Loss/cn-loh Of 16pmentioning

confidence: 67%

“…Of note, 2 cases from the Siddiqi et al study were not included, as those cases had demonstrable BCL2/IGH rearrangements. The aggregate frequencies of particular alterations found in dFL were contrasted with previously published reports for cFL (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and MZL (26,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Although the previous studies describing CNVs in cFL used a variety of techniques, most of these studies (8/13, 61%) were performed using SNP-array platforms similar to the present method indicating that the results obtained in these prior studies should be comparable to our findings.…”

Section: Crebbp and Stat6 Co-mutation And 16p13 And 1p36 Loss Represementioning

confidence: 89%

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CREBBPandSTAT6co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

Xian

Xie

Haley

et al. 2020

Preprint

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The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through gold-standard pathologic review, FISH, SNP-microarray and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA co-deletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/CN-LOH, STAT6 mutation, and CREBBP and STAT6 co-mutation in dFL, as compared to conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.

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Section: Our Data Demonstrated New Associations Of Loss/cn-loh Of 16pmentioning

confidence: 67%

Section: Crebbp and Stat6 Co-mutation And 16p13 And 1p36 Loss Represementioning

confidence: 89%

CREBBPandSTAT6co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

Xian

Xie

Haley

et al. 2020

Preprint

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“…Targeted sequencing of 20 NMZL cases also showed recurrent mutations in TNFAIP3 (30%), and CD79B (10%) . A WES study of 25 NMZL cases confirmed recurrent mutations in KMT2D (28%), KLF2 (12%), and TNFAIP3 (12%), as well as TET2 (20%), CREBBP (20%), BRAF (16%), EZH2 (16%) and TBFRSF14 (16%) . Gene expression profiling from a test set of 15 NMZL and 61 validation cases revealed a molecular signature enriched for interleukins (IL‐2, IL‐6, IL‐10), integrins, PI3K, NF‐kB, and TGF‐β .…”

Section: Introductionmentioning

confidence: 91%

Deletion 20q12 is associated with histological transformation of nodal marginal zone lymphoma to diffuse large B‐cell lymphoma

et al. 2019

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The genetic and molecular abnormalities underlying histological transformation (HT) of nodal marginal zone lymphoma (NMZL) to diffuse large B-cell lymphoma (DLBCL) are not well known. While del(20q12) is commonly deleted in myelodysplastic syndrome it has not previously been associated with DLBCL. We recently described a case of DLBCL harboring del(20q12) in a patient with a history of MZL involving lymph nodes and skin. Here we report eight matched cases of transformed MZL(tMZL): six from nodal MZL (tNMZL) and two from splenic MZL (tSMZL). We found >20% del(20q12) in 4/6 tNMZL, but not in tSMZL, nor in unmatched DLBCL, MZL with increased large cells (MZL-ILC), or MZL cases. To examine whether transformation is associated with a specific gene signature, the matched cases were analyzed for multiplexed gene expression using the Nanostring PanCancer Pathways panel. The differential gene expression signature revealed enrichment of inflammatory markers, as previously observed in MZL. Also, tMZL and de novo DLBCL were enriched for extracellular matrix proteins such as collagen and fibronectin, vascular development protein PDGFRβ, DNA repair protein RAD51, and oncogenic secrete protein Wnt11. A subset of genes is expressed differentially in del(20q12) tMZL cases vs non-del(20q12) tMZL cases. These results suggest a specific pathway is involved in the histological transformation of NMZL, which could serve as an indicator of aggressive clinical course in this otherwise indolent neoplasm.

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“…Using this rubric, each variant was assigned into one of four categories: likely somatic, cannot exclude somatic/possibly somatic, cannot exclude somatic/possibly germline, and likely germline. Within the "cannot exclude somatic" category, variants were grouped into the possibly germline category if the gene in question had not been reported to be mutated in either dFL 20,21 , pFL 25 , cFL 14,19 , or MZL 26 . Variants assigned to the "likely somatic" and "cannot exclude somatic/possibly somatic" categories were included for further analyses.…”

Section: Targeted Next-generation Sequencing Analysismentioning

confidence: 99%

CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

et al. 2020

View full text Add to dashboard Cite

The diffuse variant of follicular lymphoma (dFL) is a rare variant of FL lacking t(14;18) that was first described in 2009. In this study, we use a comprehensive approach to define unifying pathologic and genetic features through goldstandard pathologic review, FISH, SNP-microarray, and next-generation sequencing of 16 cases of dFL. We found unique morphologic features, including interstitial sclerosis, microfollicle formation, and rounded nuclear cytology, confirmed absence of t(14;18) and recurrent deletion of 1p36, and showed a novel association with deletion/CN-LOH of 16p13 (inclusive of CREBBP, CIITA, and SOCS1). Mutational profiling demonstrated near-uniform mutations in CREBBP and STAT6, with clonal dominance of CREBBP, among other mutations typical of germinal-center B-cell lymphomas. Frequent CREBBP and CIITA codeletion/mutation suggested a mechanism for immune evasion, while subclonal STAT6 activating mutations with concurrent SOCS1 loss suggested a mechanism of BCL-xL/BCL2L1 upregulation in the absence of BCL2 rearrangements. A review of the literature showed significant enrichment for 16p13 and 1p36 loss/ CN-LOH, STAT6 mutation, and CREBBP and STAT6 comutation in dFL, as compared with conventional FL. With this comprehensive approach, our study demonstrates confirmatory and novel genetic associations that can aid in the diagnosis and subclassification of this rare type of lymphoma.

show abstract

High-throughput sequencing of nodal marginal zone lymphomas identifies recurrent BRAF mutations

Cited by 58 publications

References 75 publications

CREBBPandSTAT6co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

CREBBPandSTAT6co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

Deletion 20q12 is associated with histological transformation of nodal marginal zone lymphoma to diffuse large B‐cell lymphoma

CREBBP and STAT6 co-mutation and 16p13 and 1p36 loss define the t(14;18)-negative diffuse variant of follicular lymphoma

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