No abstract

Diffuse large B-cell lymphoma is the most frequent type of B-cell lymphoma in adult patients but also occurs in children. Patients are currently assigned to therapy regimens based on arbitrarily chosen age limits only (eg, 18 or 60 years) and not biologically justified limits. A total of 364 diffuse large B-cell lymphomas and related mature aggressive B-cell lymphomas other than Burkitt lymphoma from all age groups were analyzed by comprehensive molecular profiling. The probability of several biologic features previously reported to be associated with poor prognosis in diffuse large B-cell lymphoma, such as ABC subtype, BCL2 expression, or cytogenetic complexity, increases with age at diagnosis. Similarly, various genetic features, such as IRF4 translocations, gains in 1q21, 18q21, 7p22, and 7q21, as well as changes in 3q27, including gains and translocations affecting the BCL6 locus, are significantly associated with patient age, but no cut-offs between age groups could be defined. If age was incorporated in multivariate analyses, genetic complexity lost its prognostic significance, whereas the prognostic impact of ABC subtype and age were additive. Our data indicate that aging is a major determinant of lymphoma biology. They challenge current concepts regarding both prognostic biomarkers and treatment stratification based on strict age cut-offs. (Blood. 2012;119(8): 1882-1887)

© F e r r a t a S t o r t i F o u n d a t i o nN o c o m m e r c i a l u s e software (Biodiscovery, El Segundo, CA, USA). Gains and losses were evaluated by 2 different observers. Fluorescence in situ hybridization (FISH) analyses were performed for the detection of breakpoints or gene fusions and for verification of gains in chromosome 6p25 as previously described. 9,10 For this purpose, commercially available MYC BAP, BCL2 BAP, IGH BAP and BCL6 BAP probes, an IGH/BCL2 doublecolor double-fusion probe (all Abbott/Vysis, Downers Grove, IL, USA) and a previously designed FISH probe for IRF4 (BAP) 4 were used.Potential point mutations detected by MIP-assay in PIK3CA, FBXW7, ABL1, NOTCH1, STK11 and PTEN were also analyzed by direct sequencing using ABI PRISM 3100 Genetic Analyzer system (Applied Biosystems, Foster City, CA, USA). Details are described in the Online Supplementary Appendix. Similarly, the coding exons of TNFRSF14 (Online Supplementary Table S2) and Tyr641 EZH2 4 were also analyzed by direct sequencing in the whole series.Clonality analysis was performed investigating the framework 1-3 regions of the immunoglobulin heavy chain (IGH) according to the Biomed-2 protocol. 11Statistical analyses were performed using PASW Statistics software version 18 (SPSS Inc., Chicago, IL, USA).The study was performed in the framework of the BFM-NHL trial, for which central and local institutional review board (IRB) approvals were obtained, and according to the guidelines of the MMML Network Project of the Deutsche Krebshilfe (approved by the Institutional Review Board of the Medical Faculty Kiel under 403/05). Results and DiscussionPediatric FL is a rare disease that differs from its adult counterpart both genetically and clinically. 3 We recently described a distinct subset of germinal center B-cell lymphomas including FL characterized by the presence of IRF4 gene translocations, predominately affecting children I. Martin-Guerrero et al. 1238haematologica | 2013; 98(8) Germline homozygosity (e.g. AA, BB alleles) at a given SNP results in calls at the 0 and 1 levels, respectively, germline heterozygosity (AB-alleles) in calls around 0.5 (y-Axis: 0-1). CNN-LOH in the tumor leads to loss of calls around 0.5 and to the presence of allelic imbalance calls derived from a sum of heterozygous normal cell (AB) and homozygous tumor cell (AA or BB) calls for a given locus resulting in values between 0-0.5 or 0.5-1 depending on the amount of cells carrying the aberration. Thus, in the areas with only contribution from one parent (LOH/CNN-LOH), two bands should we expected (0% and 100%->0 and 1.0. y Axis). In the 3 cases (pFL7, pFL10, pFL14), the probes did not reach such thresholds because alterations are detected to be in mosaicism (not germline alterations .4 In the present study, we determined genetic aberrations in a series of 18 pediatric FL cases lacking such IRF4 translocation. Of these 18 FL, 9 (50%) were classified as FL grade 3a (FL3a), 6 (33%) as grade 3b (FL3b), one (6%) as grade 3 unclassified, and 2 (11...