scholarly journals The molecular ontogeny of follicular lymphoma: gene mutations succeeding the BCL2 translocation define common precursor cells

2021 ◽  
Author(s):  
Sarah Haebe ◽  
William Keay ◽  
Stefan Alig ◽  
Anne‐Wiebe Mohr ◽  
Larissa K. Martin ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Gene Mutations ◽  
Precursor Cells ◽  
Common Precursor

The promises and challenges of using gene mutations for patient stratification in follicular lymphoma

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1491-1498 ◽  
Author(s):  
Oliver Weigert ◽  
David M. Weinstock
Keyword(s):  
Follicular Lymphoma ◽  
Risk Model ◽  
Model Development ◽  
Gene Mutations ◽  
Predictive Biomarkers ◽  
Individual Risk ◽  
Patient Stratification ◽  
Risk Models ◽  
Risk Patients ◽  
Selection Of

Abstract Follicular lymphoma (FL) is a clinically and molecularly highly heterogeneous disease. Most patients achieve long-lasting remissions and have excellent overall survival (OS) with current treatment. However, ∼20% of patients have early progression of disease and short OS. At present, therapies are not guided by individual risk or disease biology. Reliable tools for patient stratification are urgently needed to avoid overtreatment of low-risk patients and to prioritize alternative approaches in high-risk patients. A rapidly expanding repertoire of promising therapeutic options is available for clinical evaluation; however, the numbers of patients with FL and the resources to conduct adequately powered trials are limited. Recent studies have shown that gene mutations can serve as prognostic and/or predictive biomarkers, in particular when integrated into composite risk models. Before translating these findings into routine clinical practice, however, several challenges loom. We review aspects of “clinicogenetic” risk model development and validation that apply to FL and more generally to other cancers. Finally, we propose a crowdsourcing effort that could expedite the development, validation, refinement, and selection of risk models. A new era of collaboration and harmonization is required if we hope to transition from empiric selection of therapeutics to risk-based, biology-guided treatment of patients with FL.

Genetic markers for lung and esophagus common precursor cells in human development

2015 ◽  
Vol 463 (1) ◽  
pp. 203-208 ◽  
Author(s):  
M. V. Zinovyeva ◽  
M. B. Kostina ◽  
G. S. Monastyrskaya ◽  
A. V. Sass ◽  
O. B. Filyukova ◽  
...  
Keyword(s):  
Human Development ◽  
Genetic Markers ◽  
Precursor Cells ◽  
Common Precursor

scholarly journals FOXP1 expression is a prognostic biomarker in follicular lymphoma treated with rituximab and chemotherapy

Blood ◽  
2018 ◽  
Vol 131 (2) ◽  
pp. 226-235 ◽  
Author(s):  
Anja Mottok ◽  
Vindi Jurinovic ◽  
Pedro Farinha ◽  
Andreas Rosenwald ◽  
Ellen Leich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Follicular Lymphoma ◽  
Prognostic Biomarker ◽  
Gene Mutations ◽  
High Expression ◽  
Specific Gene ◽  
Key Points

Key Points High expression of FOXP1 predicts adverse FFS in patients with FL treated with immunochemotherapy. FOXP1 high and low expressors differ in specific gene mutations and gene expression changes.

scholarly journals Epigenetics of Indolent Lymphoma and How It Drives Novel Therapeutic Approaches—Focus on EZH2-Targeted Drugs

2021 ◽  
Vol 23 (7) ◽  
Author(s):  
Jemma Longley ◽  
Peter W. M. Johnson
Keyword(s):  
Follicular Lymphoma ◽  
Gene Mutations ◽  
Tumour Microenvironment ◽  
Indolent Lymphoma ◽  
Wild Type ◽  
Therapeutic Approaches ◽  
Epigenetic Modifier ◽  
Attractive Option ◽  
Early Phase Clinical Trials ◽  
Target Effects

Abstract Purpose of Review Epigenetic modifier gene mutations are common in patients with follicular lymphoma. Here we review the pathogenesis of these mutations and how they are targeted by epigenetic drugs including EZH2 inhibitors in both mutated and wild-type disease. Recent Findings The use of EZH2 inhibitor tazematostat in early phase clinical trials has proved encouraging in the treatment of follicular lymphoma harbouring an EZH2 mutation; however, responses are also seen in patients with wild-type disease which is partially explained by the off target effects of EZH2 inhibition on immune cells within the tumour microenvironment. Summary Further studies incorporating prospective molecular profiling are needed to allow stratification of patients at both diagnosis and relapse to further our understanding of how epigenetic modifier mutations evolve over time. The use of tazematostat in combination or upfront in patients with an EZH2 mutation remains unanswered; however, given durable responses, ease of oral administration, and tolerability, it is certainly an attractive option.

scholarly journals Chromatin modifying gene mutations in follicular lymphoma

Blood ◽  
2018 ◽  
Vol 131 (6) ◽  
pp. 595-604 ◽  
Author(s):  
Michael R. Green
Keyword(s):  
Follicular Lymphoma ◽  
Germinal Center ◽  
Gene Mutations ◽  
Significant Heterogeneity ◽  
B Cell Differentiation ◽  
Disease Biology ◽  
Sequencing Studies ◽  
Target Disease ◽  
Attractive Therapeutic Target ◽  
Functional Consequences

Abstract Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next-generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease. Understanding the complex roles of these mutations will be central to identifying and adaptively targeting associated vulnerabilities. Recent studies have provided insight into the functional consequences of the most frequently mutated CMGs (KMT2D, CREBBP, and EZH2) and point to a role for these events in modifying normal B-cell differentiation programs and impeding germinal center exit. However, the majority of FL tumors serially acquire multiple CMG mutations, suggesting that there is a level of cross talk or cooperation between these events that has not yet been defined. Here, I review the current state of knowledge on CMG mutations in FL, discuss their potential as therapeutic targets, and offer my perspective on unexplored areas that should be considered in the future.

scholarly journals Genomic landscape of cutaneous follicular lymphomas reveals 2 subgroups with clinically predictive molecular features

2021 ◽  
Vol 5 (3) ◽  
pp. 649-661
Author(s):  
Xiaolong Alan Zhou ◽  
Jingyi Yang ◽  
Kimberly G. Ringbloom ◽  
Maria Estela Martinez-Escala ◽  
Kristen E. Stevenson ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Systemic Disease ◽  
Gene Mutations ◽  
Proliferation Index ◽  
Copy Number Loss ◽  
Loss Of Function ◽  
Molecular Features ◽  
Systemic Spread ◽  
Genetic Features ◽  
Follicular Lymphomas

Abstract Primary cutaneous follicle center lymphomas (PCFCLs) are indolent B-cell lymphomas that predominantly remain skin restricted and manageable with skin-directed therapy. Conversely, secondary cutaneous involvement by usual systemic follicular lymphoma (secondary cutaneous follicular lymphoma [SCFL]) has a worse prognosis and often necessitates systemic therapy. Unfortunately, no histopathologic or genetic features reliably differentiate PCFCL from SCFL at diagnosis. Imaging may miss low-burden internal disease in some cases of SCFLs, leading to misclassification as PCFCL. Whereas usual systemic FL is well characterized genetically, the genomic landscapes of PCFCL and SCFL are unknown. Herein, we analyzed clinicopathologic and immunophenotypic data from 30 cases of PCFCL and 10 of SCFL and performed whole-exome sequencing on 18 specimens of PCFCL and 6 of SCFL. During a median follow-up of 7 years, 26 (87%) of the PCFCLs remained skin restricted. In the remaining 4 cases, systemic disease developed within 3 years of diagnosis. Although the SCFLs universally expressed BCL2 and had BCL2 rearrangements, 73% of the PCFCLs lacked BCL2 expression, and only 8% of skin-restricted PCFCLs had BCL2 rearrangements. SCFLs showed low proliferation fractions, whereas 75% of PCFCLs had proliferation fractions >30%. Of the SCFLs, 67% had characteristic loss-of-function CREBBP or KMT2D mutations vs none in skin-restricted PCFCL. Both SCFL and skin-restricted PCFCL showed frequent TNFRSF14 loss-of-function mutations and copy number loss at chromosome 1p36. These data together establish PCFCL as a unique entity with biological features distinct from usual systemic FL and SCFL. We propose 3 criteria based on BCL2 rearrangement, chromatin-modifying gene mutations (CREBBP, KMT2D, EZH2, and EP300), and proliferation index to classify cutaneous FL specimens based on the likelihood of concurrent or future systemic spread.

Targeted Sequencing Reveals Novel Gene Mutations Associated with Transformation and Early Progression in Follicular Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2919-2919
Author(s):  
Robert Kridel ◽  
Fong Chun Chan ◽  
Anja Mottok ◽  
Merrill Boyle ◽  
Pedro Farinha ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Progressive Disease ◽  
High Risk Patient ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Aggressive Lymphoma ◽  
Lower Sensitivity ◽  
Histological Transformation ◽  
Early Progression

Abstract Introduction : Follicular lymphoma (FL) remains an incurable malignancy as patients eventually experience progressive disease. A subset of patients is at risk of early lymphoma-related mortality due to histological transformation (TFL) to aggressive lymphoma (2-3% of patients per year) or early progression after immuno-chemotherapy, each of which leads to shortened survival. Mutations associated with transformation and/or early progression have been reported in the literature (e.g. CDKN2A, TP53, B2M) and the m7-FLIPI clinico-genetic risk model defines a high-risk patient group with poor failure-free survival after first-line treatment. However, the current knowledge of genetic alterations underlying transformation and/or early progression is inadequate to explain the majority of transformed cases and accurately predict early progressive disease. Materials and Methods: We performed targeted capture-based sequencing of 94 genes in a large cohort of fresh-frozen and formalin-fixed and paraffin-embedded patient specimens (402 samples in total). This cohort comprised 277 samples from 159 patients that experienced transformation (including 128 samples at T1 (the time of FL) and 149 samples at T2 (the time of transformation) with 118 paired biopsies) and 125 samples from 125 patients (pre-treatment samples only) presenting with either early progression within 2.5 years after starting immunochemotherapy (n=41) or late or never progression for at least 5 years after starting immunochemotherapy or observation (n=84). Mutations were called using MutationSeq and putative single nucleotide polymorphisms were filtered out using either matching germline samples (n=84) or dbSNP (v147). Bayesian proportion tests were used to compare the prevalence of gene mutations between groups. Results : We first compared T1 (n=128) and T2 (n=149) samples from 159 patients experiencing transformation. Eleven genes were more commonly altered in transformed lymphoma. These included genes that had previously been associated with transformation, such as TP53, B2M, MYC and EBF1, as well as genes that have not yet been implicated as contributing to this process, for example EZH2, CCND3, PIM1 and ITPKB. Moreover, mutations in GNA13, S1PR2 and P2RY8, that have been implicated in dissemination of germinal centre B cells, were enriched in T2 samples. In addition, cell-of-origin classification was available for 108 of the TFL cases with DLBCL histology, 18 and 90 of which were of the ABC and GCB subtype, respectively. Although the number of ABC-TFL cases was small, we observed higher percentages of BCL10 (16% versus 1%, Fisher P=0.004), CD79B (22% versus 4%, Fisher P=0.005) and MYD88 mutations (28% versus 9%, P=0.006) in ABC-TFL than in GCB-TFL, suggesting that B-cell receptor signaling and NF-κB signaling are important contributors to the ABC phenotype in TFL. Next, we assessed the association of gene mutations with patient outcomes contrasting early progressers (n=41) and late or non-progressers (n=84). Eleven genes were mutated more commonly in early progressers than in late progressers, including KMT2C, TP53, BTG1, MKI67, XBP1 and SOCS1. Overall, 32 out of 41 early progressers (78%) had mutations in at least one of the 11 early progression-associated genes, but none of the individual early progression-associated genes were mutated at a frequency > 22%. Thus, early progression appears to be related to relatively infrequent genetic alterations. None of the early progression-associated gene mutations form part of the m7-FLIPI outcome predictor. Furthermore, in our cohort that was enriched for clinical extremes, the m7-FLIPI was similarly associated with early progression when compared to the FLIPI but it was not superior, having higher specificity (89% versus 76%), but lower sensitivity (36% versus 63%). Conclusions: We found novel associations of gene mutations with transformation and showed that TFL is molecularly heterogeneous, with the ABC subtype being characterized by differential gene mutation when compared to the GCB subtype. With regards to progressive disease after immuno-chemotherapy, our approach identified early progression as a distinct clinico-genetic disease category that is imperfectly captured by traditional prognostic tools. Disclosures Connors: Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Millennium Takeda: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.

scholarly journals p53 mutations are associated with histologic transformation of follicular lymphoma

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2289-2295 ◽  
Author(s):  
F Lo Coco ◽  
G Gaidano ◽  
DC Louie ◽  
K Offit ◽  
RS Chaganti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Low Grade ◽  
Diffuse Type ◽  
P53 Mutations ◽  
Clinical Progression ◽  
Hodgkin's Lymphomas

Abstract The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.

Classical Hodgkin's Disease and Follicular Lymphoma Originating From the Same Germinal Center B Cell

1999 ◽  
Vol 17 (12) ◽  
pp. 3804-3809 ◽  
Author(s):  
Theresa Marafioti ◽  
Michael Hummel ◽  
Ioannis Anagnostopoulos ◽  
Hans-Dieter Foss ◽  
Dieter Huhn ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Light Chain ◽  
Germinal Center ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Immunoglobulin Genes ◽  
Lymphoma Cells ◽  
Common Precursor ◽  
Germinal Center B Cell

PURPOSE: Classical Hodgkin's disease and non-Hodgkin's B-cell lymphoma occasionally occur in the same patient. To clarify whether these different diseases share a common precursor cell, we analyzed the immunoglobulin rearrangements in tumor cells of the classical Hodgkin's disease and the follicular lymphoma that developed in the same patient 2 years apart. PATIENTS AND METHODS: Polymerase chain reaction (PCR) for the detection of rearranged immunoglobulin genes was carried out on single Reed-Sternberg cells and on whole tissue DNA extracted from the follicular lymphoma. PCR products were sequenced and compared with each other and with germ line immunoglobulin variable segments. Immunoglobulin heavy- and light-chain transcripts were analyzed by radioactive in-situ hybridization. RESULTS: The same monoclonal immunoglobulin gene rearrangement was found in both neoplasms. The variable region of the immunoglobulin heavy-chain genes of the Reed-Sternberg and of the follicular lymphoma cells were differently mutated, but six somatic mutations were shared by both lymphoma cells. Although the coding capacity of the immunoglobulin genes was preserved in both neoplastic cell populations, immunoglobulin heavy- (μ) and light- (κ) chain expression was restricted to the follicular lymphoma cells, except for small amounts of kappa light-chain mRNA in some Reed-Sternberg cells. CONCLUSIONS: The neoplastic cells of the Hodgkin's disease and the follicular lymphoma that occurred in this patient derived from a common precursor B cell. Its differentiation stage could be identified as that of a germinal center B cell. Thus, transforming events can be more important than the cell of origin in determining a disease entity.

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