Comparative analysis of primary <i>versus</i> relapse/refractory DLBCL identifies shifts in mutation spectrum

Greenawalt, Danielle M.; Liang, Winnie S.; Saif, Sakina; Johnson, Justin; Todorov, Petar; Dulak, Austin; Enríquez, Daniel; Halperin, Rebecca F.; Ahmed, Ambar; Saveliev, Vladislav; Carpten, John D.; Craig, David W.; Barrett, J. Carl; Dougherty, Brian; Zinda, Michael; Fawell, Stephen E.; Dry, Jonathan R.; Byth, Kate

doi:10.18632/oncotarget.18502

Cited by 29 publications

(43 citation statements)

References 42 publications

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“…11 In addition to comparing mutation prevalence between untreated DLBCL and rrDLBCL, some studies compared the clonal population structure and mutation burden between paired diagnostic and relapse samples. 11,12 Such analyses identified additional candidate genes whose mutation could contribute to treatment resistance, such as BCL2 and CREBBP, 11 but these results have not been independently confirmed. The genetic heterogeneity of DLBCL warrants a comprehensive study of rrDLBCL to definitively identify genes whose mutation may afford resistance to components of R-CHOP.…”

Section: Introductionmentioning

confidence: 99%

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma

et al. 2020

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Diffuse large B-cell lymphoma (DLBCL) patients are typically treated with immunochemotherapy containing rituximab (rituximab, cyclophosphamide, hydroxydaunorubicin-vincristine (Oncovin), and prednisone [R-CHOP]); however, prognosis is extremely poor if R-CHOP fails. To identify genetic mechanisms contributing to primary or acquired R-CHOP resistance, we performed target-panel sequencing of 135 relapsed/refractory DLBCLs (rrDLBCLs), primarily comprising circulating tumor DNA from patients on clinical trials. Comparison with a metacohort of 1670 diagnostic DLBCLs identified 6 genes significantly enriched for mutations upon relapse. TP53 and KMT2D were mutated in the majority of rrDLBCLs, and these mutations remained clonally persistent throughout treatment in paired diagnostic-relapse samples, suggesting a role in primary treatment resistance. Nonsense and missense mutations affecting MS4A1, which encodes CD20, are exceedingly rare in diagnostic samples but show recurrent patterns of clonal expansion following rituximab-based therapy. MS4A1 missense mutations within the transmembrane domains lead to loss of CD20 in vitro, and patient tumors harboring these mutations lacked CD20 protein expression. In a time series from a patient treated with multiple rounds of therapy, tumor heterogeneity and minor MS4A1-harboring subclones contributed to rapid disease recurrence, with MS4A1 mutations as founding events for these subclones. TP53 and KMT2D mutation status, in combination with other prognostic factors, may be used to identify high-risk patients prior to R-CHOP for posttreatment monitoring. Using liquid biopsies, we show the potential to identify tumors with loss of CD20 surface expression stemming from MS4A1 mutations. Implementation of noninvasive assays to detect such features of acquired treatment resistance may allow timely transition to more effective treatment regimens.

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Section: Introductionmentioning

confidence: 99%

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma

et al. 2020

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“…NFKBIZ sSNVs were reported to be enriched in relapse specimens [30]. Two independent studies found NFKBIE to be the target of an identical frameshift 4-bp deletion in three cases [30,51]. This same frameshift deletion was also detected in the primary samples of untreated DLBCL patients [30] and in aggressive chronic lymphocytic leukemia [52].…”

Section: Common Alterations In Relapse/refractory Dlbcl and Transformmentioning

confidence: 87%

Novel insights into the disease dynamics of B‐cell lymphomas in the Genomics Era

Chan

Lim

Kridel

2018

The Journal of Pathology

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High-throughput sequencing has significantly contributed to revealing the molecular underpinnings of B-cell lymphomagenesis and disease progression. It is now a widely accepted concept that the diversity of clinical responses to front-line therapy and the development of relapsed/refractory disease are in part explained by 'inter-patient' genetic heterogeneity measurable by individual sets of somatic gene alterations in tumor genomes. Moreover, extensive 'intra-tumor' heterogeneity on the genotypic and phenotypic levels is the product of ongoing tumor evolution and adaptation to various selective pressures during cancer initiation, progression, and therapeutic intervention. As the management of disease progression remains one of the most significant clinical challenges, it is becoming increasingly important to delineate how B-cell lymphomas evolve over time and to develop progression-related biomarker assays. Toward this goal, recent investigations have moved from studying lymphoma biology at initial diagnosis to doing so at multiple time points during the disease course. Profiling progressed tumors, and in particular paired biopsies at initial diagnosis and disease progression of the same patients, has led to novel insights into clonal tumor evolution and tumor microenvironment dynamics. This review discusses the latest findings on genomic alterations and microenvironment biology associated with relapsed/refractory B-cell lymphomas, with a particular emphasis on alterations that are acquired or become more prevalent at disease progression. We also describe overarching tumor evolution patterns, and highlight emerging precision medicine methodologies that can aid in an improved understanding and management of relapsed/refractory disease.

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“…con rmed the data. In the end, we selected 4 articles from 1495 articles (Table 1) [4][5][6][7], and the data came from 5 independent clinical studies. We extracted the following information from eligible studies: rst author, year of publication, journal, pathological subtypes of RRDLBCL, and whole-exome sequencing results (mutated genes, mutation types, etc.)…”

Section: Study Selectionmentioning

confidence: 99%

“…At present, there are not enough large-scale studies to summarize the genetic characteristics of this particular population of RRDLBCL patients. To address this, we screened 1495 documents, from which we summarized whole-exome sequencing data from 4 studies of RRDLBCL [4][5][6][7]. By conducting an association study of whole-exome sequencing results for a total of 92 patients, we observed the most common mutations in RRDLBCL and attempted to cluster them.…”

Section: Introductionmentioning

confidence: 99%

Genetic Map of Relapsed and Refractory Diffuse Large B-cell Lymphoma: A Systemic Review and Association Analysis

Gao¹,

Tian²,

Wang³

et al. 2020

Preprint

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Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin lymphoma (NHL). In recent years, a deeper understanding of the genetic subtypes of diffuse large B lymphoma has been reached, and these advances have also been applied to research on relapsed and refractory diffuse large B-cell lymphoma (RRDLBCL). We screened 1495 documents, compiled the whole-exome sequencing data of several studies, formed a data set including 92 observations, and performed association analysis on the high-frequency mutations among them. The most common mutations in the data set include TTN (34/92, 37.0%), KMT2D (29/92, 31.5%), TP53 (25/92, 27.2%), IGLL5 (25/92, 27.2%), CREBBP (21 /92, 22.8%), BCL2 (21/92, 22.8%), MYD88 (20/92, 21.7%), and SOCS1 (19/92, 20.7%). Among these, CREBBP, KMT2D, and BCL2 have a strong association with each other, and SOCS1 has a strong association with genes such as ACTB, CIITA, and GNA13. There is also a strong association between SOCS1 and STAT6. Though TP53 and MYD88 lack significant associations with most genes, the association between MYD88 and PIM1 is significant. Through SOM clustering and expression-level analysis of common gene mutations, we believe that RRDLBCL can be divided into four main types: (1) JAK-STAT-related type, including STAT6, SOCS1, ITPKB, CIITA, and B2M. The expression lineage is similar to PMBL and cHL. (2) EZB type: BCL2 and EZHZ are the main types of mutations. Epigenetic mutations such as KMT2D and CREBBP are more common in this type, and are often accompanied by BCL2 mutations. (3) MCD type, including MYD88, CD79B and PIM1. These genes are involved in the BCR signaling pathway and related pathways, and are connected by the common NF-κB pathway. (4) Undefined type (Sparse Mutation type). These patients are mainly individuals with sparse mutations, including some patients with TP53 mutations (30.3%, 10/33), but who generally lack characteristic mutations. Among the common gene mutations, the expression changes in BCL2, PIM1, STAT6, ITPKB, and GNA13 have more significant prognostic significance. We also reviewed the literature from recent years concerning the previously mentioned common gene mutations.

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Comparative analysis of primary versus relapse/refractory DLBCL identifies shifts in mutation spectrum

Cited by 29 publications

References 42 publications

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma

Novel insights into the disease dynamics of B‐cell lymphomas in the Genomics Era

Genetic Map of Relapsed and Refractory Diffuse Large B-cell Lymphoma: A Systemic Review and Association Analysis

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