Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), patients who ...fail R-CHOP have a dismal outcome. Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. Advances in molecular genetics have vastly improved our understanding of the biological diversity of DLBCL and have led to the discovery of key oncogenic pathways. In addition to the major molecular designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing technologies have unveiled the remarkable complexity of DLBCL and identified unique molecular targets that may be differentially exploited for therapeutic benefit. These findings have translated into a growing list of promising novel agents. Moving forward, it is of paramount importance to recognize the heterogeneity of DLBCL and to investigate these targeted agents within patient populations who are most likely to benefit. It will be necessary to prioritize drugs that affect key driver pathways and to combine them rationally to optimize their benefit. Improved prognostication and the availability of predictive biomarkers will be crucial to allow for the possibility of individualized risk-adapted therapy.
Non-Hodgkin lymphoma Armitage, James O, Prof; Gascoyne, Randy D, Prof; Lunning, Matthew A, DO ...
The Lancet (British edition),
07/2017, Letnik:
390, Številka:
10091
Journal Article
Recenzirano
Summary Lymphomas can affect any organ in the body, present with a wide range of symptoms, and be seen by primary care physicians and physicians from most specialties. They are traditionally divided ...into Hodgkin's lymphoma (which accounts for about 10% of all lymphomas) and non-Hodgkin lymphoma, which is the topic of this Seminar. Non-Hodgkin lymphoma represents a wide spectrum of illnesses that vary from the most indolent to the most aggressive malignancies. They arise from lymphocytes that are at various stages of development, and the characteristics of the specific lymphoma subtype reflect those of the cell from which they originated. Since this topic was last reviewed in The Lancet in 2012, advances in understanding the biology and genetics of non-Hodgkin lymphoma and the availability of new diagnostic methods and therapies have improved our ability to manage patients with this disorder.
B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus ...on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Primary mediastinal large B-cell lymphoma (PMBCL) is a recognized non-Hodgkin lymphoma entity with unique pathologic, clinical, and molecular characteristics distinct from those of other diffuse ...large B-cell lymphomas. Immunohistochemical characterization and molecular studies strongly suggest that PMBCL is of germinal center or postgerminal center origin. Pivotal gene expression profiling work defined major deregulated pathway activities that overlap with Hodgkin lymphoma and prompted a more detailed analysis of candidate genes. In particular, the nuclear factor-κB and the Janus Kinase-Signal Transducer and Activator of Transcription signaling pathways are targeted by multiple genomic hits, and constitutive activity of both pathways can be considered molecular hallmark alterations of PMBCL. Moreover, data are emerging giving unique insight into remodeling of the epigenome that affects transcriptional regulation of a multitude of genes. More recently, the tumor microenvironment of PMBCL has shifted into focus based on a number of gene perturbations altering expression of surface molecules that contribute to immune escape. These findings highlight the importance of immune privilege in the pathogenesis of PMBCL and suggest that disrupting crosstalk between the tumor cells and the microenvironment might be a rational new therapeutic target in conjunction with traditional treatment strategies.
Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma Schmitz, Roland; Wright, George W; Huang, Da Wei ...
New England journal of medicine/The New England journal of medicine,
04/2018, Letnik:
378, Številka:
15
Journal Article
Recenzirano
Odprti dostop
Gene-expression profiling of 574 cases of diffuse large B-cell lymphoma revealed four new subtypes based on the co-occurrence of mutation patterns. The subtypes had prognostic influence beyond the ...usual clinical prognostic factors and may aid in directing targeted therapy.
rearrangement (
-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of
R on prognosis may be influenced ...by the
partner gene (immunoglobulin IG or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of
(single-, double-, and triple-hit status) in DLBCL within the context of the
partner gene.
The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the
,
,
, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes.
A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for
-R.
-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of
R was only evident in patients with a concurrent rearrangement of
and/or
and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6;
< .001).
The negative prognostic impact of
-R in DLBCL is largely observed in patients with
double hit/triple-hit disease in which
is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further.
Hodgkin's lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most patients can be cured with modern treatment strategies, although ...approximately 20% will die after relapse or progressive disease. The histologic hallmark of the disease is the presence of the characteristic Hodgkin Reed-Sternberg (HRS) cells in classical HL and so-called lymphocyte-predominant (LP) cells in nodular lymphocyte-predominant HL. HL is unique among all cancers because malignant cells are greatly outnumbered by reactive cells in the tumor microenvironment and make up only approximately 1% of the tumor. Expression of a variety of cytokines and chemokines by the HRS and LP cells is believed to be the driving force for an abnormal immune response, perpetuated by additional factors secreted by reactive cells in the microenvironment that help maintain the inflammatory milieu. The malignant HRS and LP cells manipulate the microenvironment, permitting them to develop their malignant phenotype fully and evade host immune attack. Gene expression signatures derived from non-neoplastic cells correlate well with response to initial and subsequent therapies, reflecting their functional relevance. Recent biomarker studies have added texture to clinical outcome predictors, and their incorporation into prognostic models may improve our understanding of the biologic correlates of treatment failure. Moreover, recent preclinical and clinical studies have demonstrated that the tumor microenvironment represents a promising therapeutic target, raising hope that novel treatment strategies focused on the interface between malignant and reactive cells will soon emerge.
Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological ...transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.
Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.
Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of ...HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression.
We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data.
We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy compared with DHITsig-negative patients (5-year time to progression rate, 57% and 81%, respectively; P < .001), irrespective of HGBL-DH/TH- BCL2 status. The prognostic value of DHITsig was confirmed in an independent validation cohort. DHITsig-positive tumors are biologically characterized by a putative non-light zone germinal center cell of origin and a distinct mutational landscape that comprises genes associated with chromatin modification. A new NanoString assay (DLBCL90) recapitulated the prognostic significance and RNA sequencing assignments. Validating the association with HGBL-DH/TH- BCL2, 11 of 25 DHITsig-positive-transformed follicular lymphomas were classified as HGBL-DH/TH- BCL2 compared with zero of 50 in the DHITsig-negative group. Furthermore, the DHITsig was shared with the majority of B-cell lymphomas with high-grade morphology tested.
We have defined a clinically and biologically distinct subgroup of tumors within GCB-DLBCL characterized by a gene expression signature of HGBL-DH/TH- BCL2. This knowledge has been translated into an assay applicable to routinely available biopsy samples, which enables exploration of its utility to guide patient management.
Pathogenesis of follicular lymphoma Kridel, Robert; Sehn, Laurie H; Gascoyne, Randy D
The Journal of clinical investigation
122, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most ...tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.
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