David Wrench

Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone

To investigate the cell of origin linking follicular (FL) and transformed (t-FL) lymphomas, we analyzed the somatic hypermutation (SHM) pattern of the variable region of the immunoglobulin heavy gene (IgH-VH) in 18 sequential FL/t-FL samples and a father (donor) and son (recipient), who developed FL and t-FL, after transplantation. Genealogic trees showed a pattern compatible with a common progenitor cell (CPC) origin in 13 cases. The identification of the t-FL clonotype in the previous FL sample and of the putative CPC sequence in both the FL/t-FL biopsies showed that the intraclonal diversity of FL and t-FL germinal centers (GCs) is more intricate than previously described, and all 3 clonotypes (CPC, FL, t-FL) may occur simultaneously within the same lymph node. On the basis of the father/son model, this CPC must be long-lived, providing a possible explanation for the incurable nature of this disease.

EZH2 Y641 mutations in follicular lymphoma

We would like to acknowledge Martina Seiffert, Danilo Allegra, Angela Philippen, Bettina Klohs, Lars Bullinger, Stefan Fröhling and Claudia Scholl for helpful discussions and Frederic Blond for the bioinformatics support. We would also like to acknowledge the excellent collaboration with Bernd Korn from the German Cancer Research Center core facility Genome and Proteome. This work was supported by funding from DJCLS SP 08/05, DJCLS R 06/13, the Helmholtz Alliance for Systems Biology and the Max-Eder-Nachwuchsgruppenprogramm of the Deutsche Krebshilfe (No. 107239).

Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation

Acquired homozygosity in the form of segmental acquired uniparental disomy (aUPD) has been described in follicular lymphoma (FL) and is usually due to mitotic recombination. SNP array analysis was performed with the use of the Affymetrix 10K 2.0 Gene-chip array on DNA from 185 diagnostic FL patients to assess the prognostic relevance of aUPD. Genetic abnormalities were detected in 118 (65%) of 182 patients. Number of abnormalities was predictive of outcome; more than 3 abnormalities was associated with inferior overall survival (OS; P < .03). Sites of recurrent aUPD were detected on 6p (n = 25), 16p (n = 22), 12q (n = 17), 1p36 (n = 14), 10q (n = 8), and 6q (n = 8). On multivariate analysis aUPD on 1p36 correlated with shorter OS (P = .05). aUPD on 16p was predictive of transformation (P = .03) and correlated with poorer progression-free survival (P = .02). aUPD is frequent at diagnosis of FL and affects probability of disease transformation and clinical outcome.

Stem Cell Transplantation for Non-Hodgkin's Lymphoma

Non-Hodgkins lymphoma (NHL) includes a diverse set of conditions ranging from high-grade aggressive to more indolent low-grade disease. Hematopoietic stem cell transplantation (HSCT) has a valuable role in the management of these conditions and can provide long-term remission in selected cases. This article presents the current use of allogeneic and autologous HSCT in a number of subtypes of NHL.

SNP rs6457327 in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphoma

Inherited risk determinants for follicular lymphoma (FL) have recently been described in the immune gene-rich human leukocyte antigen region on chromosome 6p. The known importance of host immune response to FL survival led us to evaluate these germline factors in FL outcome. We confirm the association of single nucleotide polymorphisms rs10484561 (P = 3.5 × 10⁻⁹) and rs6457327 (P = .008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL transformation independently of clinical variables, including the Follicular Lymphoma International Prognostic Index.

High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10−2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.

Clinical relevance of MDM2 SNP 309 and TP53 Arg72Pro in follicular lymphoma

Tumor protein 53 (TP53) is critical to cell cycle control and is the most common mutational target in germinal center lymphomas. However, these mutations occur infrequently at diagnosis (<10%) in follicular lymphoma (FL), and are more commonly associated with disease progression or transformation to

Molecular signatures in the diagnosis and management of follicular lymphoma.

Purpose of reviewAlthough karyotypic events in follicular lymphoma and its transformation to aggressive lymphoma have been well described, the underlying genetic changes have until recently remained obscure. Both germline and acquired molecular events are now known to predict disease risk and outcome, respectively. Recent developments in these fields are covered within this review. Recent findingsIdentification of a region of germline predisposition on chromosome 6p together with pesticide influence on disease-related changes suggests specific risk factors for follicular lymphoma. The profiling of S(mu) and immunoglobulin heavy-chain locus (IgH-VH) mutations in follicular lymphoma and relapse/transformed samples suggests divergent evolution from a common progenitor, whereas modular expression profiling highlights the stem cell-like origin of disease. Furthermore, methylation profiling indicates a significant epigenetic influence on disease and novel gene mutations provide exciting new targets for investigation. SummaryRecent insights into follicular lymphoma identify constitutional and environmental predisposition further unravelling the concept of a lymphoma-initiating cell and the acquired events defining this disease. The major challenge remains successful translation of these findings into routine clinical practice.

Assessing risk and improving survival in lymphoma

Lymphoma represents the sixth most common form of cancer in the UK, with non-Hodgkin lymphoma (NHL) representing 4% and Hodgkin lymphoma (HL) <1% of cases; over 13 000 lymphoma cases are diagnosed annually1,2 and its incidence, in particular NHL, has continued to rise over recent decades.3 There are now more than 40 recognised lymphoma subtypes and this contributes to its heterogeneity of clinical presentation, ranging from subtle signs and symptoms to acutely unwell cases with end-organ compromise. The recently reported Eurocare-5 study 4 addressed composite data from 30 cancer registries across Europe, including the UK, and demonstrated improvements in 5-year adjusted survival for HL and subtypes of NHL, including the two most common: diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the overall 5-year survival rate for NHL in the UK (57.4%) was inferior to the European mean (59.4%),5 so there is a pressing need to address this disparity and the factors that may be responsible. Without the signs of a classical lymphoma presentation, patients will often visit their GP many times 6 before a possible diagnosis comes to light, often resulting in delayed referral and diagnosis. Therefore, knowledge of the common signs and symptoms is crucial and may help guide GPs to recognise the disease earlier, refer on appropriately, and avoid unnecessary diagnostic delays. The final diagnosis of lymphoma always requires histological confirmation and appropriate staging investigations. The sooner this is performed, the more likely patients will be treated at the earliest possible stage of their disease, conveying a better prognosis. The National Institute for Health and Care Excellence …

Chemotherapy: maintenance rituximab for relapsed follicular lymphoma.

Rituximab has become the mainstay of systemic therapy for patients with follicular lymphoma and is associated with an improved outcome at both diagnosis and relapse, either as induction or maintenance therapy. The challenge lies in maximizing the benefit of this drug in a condition characterized by multiple relapses.