ALBERT

Description: Key Points SOX11 silencing promotes the shift from a mature B cell into the initial plasmacytic differentiation phenotype in MCL. SOX11 promotes tumor growth of MCL cells in vivo, highlighting its implication in the aggressive behavior of conventional MCL.

Description: Genomic studies have provided a complete profile of somatic mutations in chronic lymphocytic leukemia (CLL). These comprehensive approaches have revealed a relatively large number of mutated genes, the adverse prognostic value of some of which has been demonstrated in a number of reports. Recent studies have shown the clinical relevance of TP53 mutations at very low allele frequency. The presence and prognostic impact of minor mutated clones of other CLL driver genes and their clonal dynamics in the evolution of the disease is not well known. The goal of this study was to explore the presence of clonal and subclonal mutations of TP53, SF3B1, BIRC3, and ATM using an ultra-deep next-generation sequencing (NGS) strategy, to define the evolution of these subclones in different time-points of the disease, and to determine their influence in the outcome of the patients. Samples from 363 untreated CLL cases were included in this study. Copy number alterations were investigated by high density SNP-arrays or by quantitative PCR in 341 and 16 cases, respectively. Targeted ultra-deep NGS of TP53 (exons 4-10), ATM (exons 2-63), BIRC3 (exons 2-9), and SF3B1 (exons 14-16 and 18), including splicing sites, was performed using the Access-Array system (Fluidigm) and sequenced in a MiSeq equipment (Illumina). This methodology combined with a robust bioinformatic analysis based on well-known available tools allowed the identification of mutations down to 0.3% of variant allele frequency (VAF). Results obtained were fully verified by orthogonal techniques. Twelve per cent of VAF was used as threshold for the classification of clonal or subclonal mutations since 12% was the cut-off for detection of mutations by Sanger sequencing. Deletions of 11q comprising ATM or BIRC3 were found in 7% of the cases and were associated with mutations of the other ATM allele in 19/26 (73%) cases and BIRC3 in 3/23 (13%). Deletions of 17p were found in 19 (5%) cases and co-existed with TP53 mutations in 15 (79%) of them. Regarding the mutational status of the studied genes, TP53 mutations were present in 11.6% of patients (7.2% clonal, 4.4% subclonal), ATM mutations in 10% (7% clonal, 1% subclonal, 2% germline mutations considered pathogenic), SF3B1 mutations in 12% (7% clonal, 5% subclonal), and BIRC3 mutations in 4% (2% clonal, 2% subclonal). These subclonal mutations had similar molecular characteristics to their respective high-allele frequency mutations supporting a comparable pathogenic effect. In this regard, clonal and subclonal SF3B1 mutations were associated with shorter time to first treatment (TTT) independently of IGHV mutations. Clonal and subclonal TP53 mutations predicted for shorter overall survival (OS) together with the IGHV mutational status, although the impact of isolated TP53 mutations (i.e. without 17p deletion) on OS was not so evident, as has been the case in other studies. In addition, the outcome of patients with clonal and subclonal BIRC3 mutations showed a similar significant shorter OS. Regarding ATM, the effect of isolated subclonal ATM mutations could not be evaluated because of their low number, but ATM mutations as a whole had a significant impact on TTT even in the absence of 11q deletions. This study also reinforces the need to study the germline of the patients to fully characterize the ATM mutations observed in the tumors. Of note, germline variants previously described as pathogenic were associated with 11q deletions, confirming the hypothesis already suggested that these germline variants may influence disease progression through loss of the otherallele. Clonal dynamics was examined in longitudinal samples of 45 CLL patients. We confirmed the expansion of most TP53 mutated clones after therapy. However, both TP53 and SF3B1 mutations expanded also before any therapy in some patients, indicating that progressive dynamics of these clones is not only dependent on therapy selection. On the contrary, small ATM mutated clones seemed to be more stable. Although the number of cases is limited, we observed that clonal evolution in longitudinal samples had an unfavorable impact on OS. In conclusion, this study shows the presence of a high number of subclonal mutations of different driver genes in CLL and provides insights on the impact of these mutations on the outcome of the patients. These findings suggest that the characterization of the subclonal architecture may be relevant for a better management of CLL patients. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: DLBCL is biological and clinically highly heterogeneous. Although different genetic aberrations, including recurrent somatic mutations, have been described in this tumor, their clinical impact remains to be clarified. The aim of the present study was to determine somatic mutations and copy number alterations of a selected group of genes in patients with DLBCL, in order to assess their prognostic importance and to identify potential personalized targeted drugs for these patients. Methods: 150 patients (78M/72F; median age, 66 years) diagnosed with de novo DLBCL no otherwise specified at Hospital Clínic and other institutions of the GELCAB, treated with immunochemotherapy, were included in the study. An independent series of 111 patients (54M/57F; median age, 63 years), diagnosed at different Japanese and Spanish institutions, was used to validate the significant findings. Targeted next generation sequencing (NGS) of 106 representative genes related with DLBCL and Copy Number Alterations (CNA) assessment were performed. Ten functional pathways were pre-defined, including NOTCH, tumor suppressor genes, JAK/STAT, epigenome/chromatic modifier, BCR signaling, PI3K-AKT-mTOR, MAP-kinase, B-cell differentiation, immune surveillance and cell cycle alterations. Cell of origin (COO) of the tumors was established using gene expression or the Lymph2Cx assay. Genomic-guided potential therapeutic opportunities for each patient were identified in silico by a Cancer Genome Interpreter platform. Results: A total of 765 potential driver mutations were identified in 89 of the 106 genes with a slightly higher number in germinal center B-cell like (GCB) than activated B-cell-like (ABC) DLBCL subtype. The most frequently mutated genes found in 〉15% of the cases were KMT2D (MLL2), MYD88, CREBBP and TP53, with other 27 genes being mutated in 〉5% of the cases. Several genes were differentially mutated in GCB DLBCL subtype (KMT2D, CREBBP, TNFRSF14, B2M, EZH2, GNA13, FOXO1, ACTB and SOCS1) or ABC subtype (MYD88, PIM1, CD79B and PRDM1). No relevant differences were observed in the clinical features according to individual mutations or CNA. No single gene mutation predicted response to therapy. Genetic alterations in KLHL6, ETV6, SGK1, L8q12.1, CD79B, PIM1 and TP53 predicted poor OS, whereas mutations of SOCS1 were associated with better outcome. Alterations in NOTCH pathway and tumor suppressor pathway were associated with poor outcome, whereas those of JAK/STAT pathway showed favorable prognosis (see table for detailed data). NOTCH pathway (HR 2.8; p=0.006) and tumor suppressor pathway (HR 2.4; p=0.005) maintained independent significance for OS along with R-IPI (H 4.0; p=0.006) in a multivariate analysis that also included COO and beta2-microglobulin. In addition, the prognostic value of NOTCH and tumor suppressor pathways was confirmed in the independent validation series. Finally, we identified 69 cases (46%) carrying at least one genomic alteration in 9 genes considered a biomarker of drug response supported by data of early clinical trials or pre-clinical assays; tumors of additional 26 patients (17%) had at least one gene alteration that could be exploited by a drug repurposing strategy. Conclusions: Integrating the deep sequencing analysis of a panel of selected genes and CNA, we have recognized novel target genes and defined the clinical relevance of alterations of NOTCH and tumor suppressor pathways in DLBCL. Using an in silico prescription pipeline we have also identified a number of candidate drugs with potential therapeutic interactions with driver oncogenic proteins. All these findings may orient future preclinical and clinical intervention strategies in DLBCL. Table Initial features, response to therapy and outcome according to pathways´ status Table. Initial features, response to therapy and outcome according to pathways´ status Disclosures Sancho: Celltrion, Inc: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gonzalez Barca:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau; Gilead: Speakers Bureau. Ohshima:Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau; CHUGAI PHARMACEUTICAL CO.,LTD.: Research Funding, Speakers Bureau. Akashi:Sunitomo Dainippon Pharma: Consultancy; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Bristol Meyers Squibb: Research Funding; Asahi Kasei Pharma Corporation: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Shionogi & Co., Ltd: Research Funding; Astellas Pharma: Research Funding.

Description: Introduction SOX11 is a transcription factor (TF) aberrantly expressed in the majority of mantle cell lymphomas (MCLs), which is generally associated with aggressive clinical behaviour. No mutations, genetic aberrations or direct correlations with differential DNA methylation at the promoter related to its expression have been found in MCL. Deeper insights into its regulation can be found by considering the three-dimensional (3D) chromatin structure. It is becoming clear that the genome can be partitioned into 3D building blocks, topologically associated domains (TADs) and that enhancer regions likely regulate genes within their TADs by 3D contacts, but do not affect genes outside their own TADs. By mapping the 3D chromatin structure, we previously identified a distant putative SOX11 enhancer showing enhancer activity and 3D contacts with the SOX11 gene in the SOX11-positive MCL cell line Z-138, but not in the SOX11-negative MCL cell line JVM-2. Aims We aimed to deepen our understanding of the differential 3D contacts and enhancer activity previously observed at the putative SOX11 enhancer in SOX11-positive versus SOX11-negative MCL cell lines by addressing the following questions: (i) Do TAD boundaries around the SOX11 locus change between SOX11-positive and -negative MCLs? (ii) How do the 3D contacts and chromatin states at this region behave in primary MCL cases and normal B cells? (iii) Is the putative SOX11 enhancer involved in SOX11 expression in other tissues? Methods We have extended our experimental analyses of the putative SOX11 enhancer by performing (i) HiC-sequencing and 3D fluorescence in situ hybridization (3D FISH) in MCL cell lines Z-138 and JVM-2, (ii) 4C-sequencing, chromatin inmmunoprecipiation followed by deep sequencing (ChIP-seq) of 6 histone marks, an Assay for Transposase-Accessible Chromatin with deep sequencing (ATAC-seq) and chromatin state modeling by chromHMM (using the 6 histone marks) in primary MCL cases and normal naive and memory B-cells. Furthermore, we have explored the activity of this region in other SOX11 expressing cell lines studied within the ENCODE Consortium. Results HiC-sequencing in the cell lines Z-138 (SOX11-positive) and JVM-2 (SOX11-negative) showed that the SOX11 locus and its putative enhancer are located within the same TAD in both samples. Hence, shifts in TAD boundaries do not seem to underlie the differential 3D chromatin interactions between the SOX11 locus and its putative enhancer in these two cell lines. By ChIP-seq and chromatin state modeling we observed that the promoter of SOX11 is poised, i.e., carrying histone marks H3K4me3 and H3K27me3, in normal naive and memory B-cells and the SOX11-negative MCL primary case. Furthermore, we observed weak enhancer activity at the putative SOX11 enhancer in normal naive and memory B-cells and the SOX11-negative MCL primary case, but strong enhancer activity, marked by the presence of H3K27ac, only in SOX11-positive samples. In addition, by ATAC-seq we identified two specific chromatin accessible regions that potentially represent the transcription factor binding sites responsible for activation of this enhancer region in SOX11-positive MCLs. By 4C-sequencing we observed that the SOX11 locus and its putative enhancer show high 3D contacts in two other SOX11-positive MCL cell lines (GRANTA-519 and JEKO-1) and in a SOX11-positive primary MCL case, but not in a SOX11-negative primary MCL case. Furthermore, the differential 3D contacts at these regions in Z-138 and JVM-2 were confirmed by 3D FISH, which is currently being performed in primary MCL cases. Interestingly, no 3D contacts were observed in normal naive and memory B cells, indicating that although the SOX11 promoter is poised within these normal B-cell subpopulations, primed looping at these regions does not exist and seems not to explain the 3D contacts we observed in SOX11-positive MCL cell lines and primary cases. When investigating chromatin states in cell lines studied by ENCODE with an active SOX11 promoter (H1-hESC, HSMM and NHLF) none of them show activity in the identified region, suggesting that the putative SOX11 enhancer is de novo activated only in the context of MCL lymphomagenesis. Conclusions We provide new evidence that the activation of a distant SOX11 putative enhancer and its 3D contacts to the SOX11 gene, is a de novo event in SOX11-positive MCL cell lines and primary cases that is likely specific for this malignancy. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: MCL is a mature B-cell neoplasm characterized by t(11;14) (q13;q32) and cyclin D1 (CCND1) overexpression. Molecular studies have revealed other alterations in cell-cycle regulation, DNA damage response and cell survival pathways, with a landscape of somatic mutations being recently identified. CNS involvement is a well known complication, occurring in 4-26% of MCL at five years, with an ominous significance. Although different clinical variables have been identified as risk factors for CNS infiltration, the biological parameters related to this complication have not been extensively studied. The aim of the study was to explore the biological parameters associated with CNS involvement in a multicentre and retrospective series of MCL patients. Patients and Methods: 285 patients (M:74%; 64 yr) diagnosed of MCL between 1990-2014 (median survival of 4 years) were analysed. In addition to standard clinico-biological variables, IGHV mutational analysis, chromosomal alteration studies and Sanger sequencing of NOTCH1, NOTCH2, TP53, BIRC3, WHSC1, MEF2B, MLL2, TLR2 and PRDM1 were performed. Results: CNS involvement was observed in 15/285 MCL patients (5.2%), with a 5-yr risk of 9.1% (95%CI: 4.6-13.6), one patient at diagnosis, and at first or second/ulterior progressions in 7 cases each. The clinical, pathological and molecular risk factors identified are detailed in the Table. In addition to what has been already described, CNS involvement was usually observed in MCL cases with a clinical nodal presentation (p=0.05). In fact, no indolent MCL with a non-nodal presentation developed this complication during the follow-up period. No differences were observed in the risk of CNS involvement between patients treated in first-line with conventional or high-dose intense treatment (5-yr risk: 6.1%+/-6% vs. 10.7%+/-10.6%, p=ns). Regarding the biological features, no differences in terms of the IGHV mutational status were observed in cases developing CNS involvement compared to the others (75% vs. 68.7%, using 97% identity cut-off). Similarly, the IGHV gene usage of CNS involved cases corresponded to the more frequent IGHV genes observed in MCL (usually IGHV1-18, IGHV3-23, IGHV4-34, IGHV4-59). Although not significant, a predominance of high number copy number alterations (CNA) (〉4) could be observed in the genetic study of MCL cases with CNS involvement as could be expected for the enrichment in blastoid variants (up to 50% of these cases). In fact, we did not observe any case with CNS involvement among those cases with 3 or less CNA. CNS involvement was not related to common poor prognosis genetic alterations such as 9p, 11p and 17p losses, but the presence of 8q gains was associated with a higher risk of CNS involvement (p=0.05). We did not find any significant association between CNS involvement and the large number of oncogenic mutations studied. Conclusions: CNS involvement in MCL is associated with initial aggressive clinico-biological characteristics. Non-nodal MCL cases with a low number of genetic alterations did not present CNS involvement. Finally, the presence of 8q gains was associated with a higher risk of CNS infiltration. Table Initial Clinical Features Category N 5 yr-CNS involvement (%, 95%CI) HR p Performance status (ECOG) 〉 1 8/51 41.5 (+/-28) 4.2 .003 ≤ 1 7/128 9.4 (+/-5.5) Nodal disease Yes 14/185 13.3 (+/-7.6) 6.1 .05 No 1/77 1.4 (+/-2.7) Hemoglobin (g/L) 〈 105 12/93 24.7 (+/-14.7) 3.2 .05 ≥ 105 3/78 5.3 (+/-6.3) LDH 〉 ULN 4/89 27.1(+/-19.4) 6.7 ULN 11/114 21.6 (+/-14.9) 3.5 .04 〈 ULN 3/66 8.7(+/-10) Molecular & Pathological data Histological variant Blastoid 6/58 17.3 (+/-13.7) 3.5 .02 Others 8/156 1.3 (+/-7.2) Ki-67 〉 30% 5/44 17.5 (+/-14.9) 3.6 .06 ≤ 30% 3/61 6.7 (+/-9.4) SOX11 Positive 8/153 2.9 (+/- 5.7) 2.6 ns Negative 1/42 2.1 (+/-2.4) IGHV ≥97% 6/109 9.5 (+/-9.6) 1.9 ns 4 2/87 3.9 (+/-5.7) 1.1 ns ≤ 4 1/44 2.3 (+/-4.3) Chromotripsis Yes 1/17 12.5 (+/-22) 3.2 ns No 2/106 1.9 (+/-2.7) 8q gain Yes 2/30 13.1(+/-19) 7.5 .05 No 2/97 1 (+/-1.96) CNA: copy number alteration; IGHV: immunoglobulin heavy chain; LDH: Lactate dehydrogenase Disclosures No relevant conflicts of interest to declare.

Description: Introduction Recent large scale genomic studies have disclosed the heterogeneity of the mutational landscape of chronic lymphocytic leukemia (CLL). The remarkable genomic plasticity of this disease has been further emphasized by the complex subclonal composition recognized in some tumors. Initial studies using high-coverage next generation sequencing (NGS) have revealed the prognostic impact of mutations at very low allelic frequency. The results of these studies have opened a new perspective where the proportion of cells carrying specific driver mutations rather than just the presence or absence of the alterations may be relevant to understand the evolution of this disease. However, the information generated has been limited to a small subset of CLL driver genes. The aims of this study were to define the deep mutational architecture of 28 frequently altered driver genes in CLL and determine the relevance of the subclonal quantitative composition in the progression of the disease. Methods Highly purified tumor samples from 406 untreated CLL patients were included in this study. Ultra-deep NGS of the 28 target genes was performed using the Acces-Array system (Fluidigm) (ATM, TP53, SF3B1, BIRC3, XPO1, RPS15, FBXW7, DDX3X, POT1, KLHL6, MGA, MYD88, IRF4, BRAF, NXF1, BCOR, ZNF292, NRAS, KRAS, CCND2, TRAF3, ZMYM3, MED12) or the Nextera-XT DNA library preparation kit (Illumina) (NOTCH1, NFKBIE, EGR2, PIM1, DTX1) before sequencing in a MiSeq (Illumina). A robust bioinformatic pipeline followed by an extensive verification process allowed the detection of mutations down to 0.3% of variant allele frequency (VAF). Copy number alterations were investigated by high density SNP-arrays in 376 cases. We calculated the cancer cell fraction (CCF) carrying each specific mutation using the PyClone algorithm. The prognostic impact of the mutations was evaluated for time to first treatment (TTFT) and overall survival from the time of sampling. Results The mutational frequency observed for virtually all genes was higher than in similar previous studies of population based CLL at diagnosis. We detected mutations with a VAF below the Sanger sequencing threshold (VAF 80%) was only identified in half of the patients (127, 49%). Convergent mutational evolution, defined as the acquisition of independent genetic mutations in the same gene, was observed in 19 (68%) of the 28 genes analyzed, being present in 66/260 (25%) mutated cases. The number of cases with convergent evolution was directly related to the global mutational frequency of the gene. The clinical relevance of the mutations appeared to be gene specific and related to the quantitative magnitude of the different subclones. We identified three major patterns of specific gene CCF that influenced the prognosis of the patient: 1) CCF independent pattern in which the mere detection of a mutation at any CCF conferred an adverse prognosis (TP53, ATM, POT1, NFKBIE, XPO1, or RPS15 among others); 2) CCF gradual pattern in which the poor prognostic impact was a continuous variable directly related to the size of the mutated clone (SF3B1); and 3) CCF clonal pattern in which the prognostic impact of the mutations was a categorical variable defined by a certain threshold of the mutated clone (NOTCH1, BIRC3, EGR2, FBXW7). On the other hand, cases with convergent mutational evolution had a tendency to a shorter TTFT when compared to mutated cases without this phenomenon. Conclusions In conclusion, the emergence of subclonal mutations is a general and dynamic phenomenon in CLL that seems to involve virtually all driver genes and occurs at different time points of the disease. The clinical impact of the clonal architecture of the tumor is gene specific and related to the magnitude of the respective subclone. These findings provide new insights on the relevance of the subclonal mutational profile in CLL and the importance of quantitative mutational analyses for the management of the patients. Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND Pediatric aggressive large B-cell lymphomas (LBCL) share morphological and phenotypic features with adult types but seem to have better prognosis. Additionally, a specific subtype carrying IRF4 translocations (LBCL-IRF4) has been recently identified in this age group. In adults, the cell-of-origin (COO) distinction of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures (germinal center B-cell like, GCB and activated B-cell like, ABC) and more recently clusters of genetic alterations have identified molecularly distinct DLBCL subsets that may benefit from novel therapeutic targets. The integration of pediatric population in these clinically relevant molecular subgroups and its clinical importance is not well known. The aim of this study was to characterize the molecular heterogeneity of LBCL in pediatric and young adult patients and evaluate their potential clinical impact. DESIGN Sixty-one LBCL diagnosed in patients ≤25 years-old (median age 14 years old, male/female 38/23) were included in the study. Molecular analyses included fluorescence in situ hybridization for MYC, BCL2, IRF4 and BCL6, copy number (CN) analysis (Oncoscan, Affymetrix), COO Lymph2Cx assay (NanoString) and targeted next generation sequencing of 96 B-cell lymphoma driver genes (SureSelect XT, Agilent Technologies). CNA and mutational profiles were compared to those previously published in adult DLBCL. Correlation of molecular features and event free survival (EFS) was performed using Kaplan-Meier curves. RESULTS Histologically, 33 were DLBCL, 20 LBCL-IRF4 and 8 high grade B-cell lymphomas, not otherwise specified (HGBCL). Nodal disease was present in 57%, mainly in the cervical region. COO distribution was: 68% GCB, 18% ABC and 13% unclassified. Most of LBCL-IRF4 cases were GCB-COO (73%). The IRF4 translocation was demonstrated in 16 out of 19 cases diagnosed as LBCL-IRF4 and an IGH rearrangement was seen in the other 3. Five cases carried MYC-breaks (3 DLBCL and 2 HGBCL) and two cases carried BCL6-breaks (1DLBCL and 1HGBCL). BCL2 rearrangements were absent. CN analysis detected alterations in 46/51 cases with recurrent gains (〉15%) of 1q, 2p16, 11q, trisomies 7 and 12, and recurrent losses (〉10%) of 1p36, 6q21-q22, 15q24, 17p13 and 19p13. Recurrent homozygous deletions were observed at 19p13/CD70 (6 cases), 9p13/CDKN2A (3 cases) and 13q14/RB1 (2 cases). Alteration patterns suggestive of chromothripsis were found in 10% (5/51) of the cases. No ABC-DLBCL related alterations such as 3p21-p14, 6q21-q25, 9p21.3 and 17p13 losses were seen. Targeted sequencing detected a total of 434 variants in 44 of 47 cases (mean 9.2 mutations/case). A pipeline for selection of driver mutations revealed a total of 270 mutations (62%) with potential functional effect. Recurrent mutations found in 〉15% of the cases affected IRF4, SOCS1, PIM1, CARD11, ACTB and CCND3 genes. In comparison to adult DLBCL, pediatric and young adult cases had significantly lower incidence of MYD88 (5 cases), CREBBP,TP53 (3 cases each) and TNFRSF14 (2 cases) mutations which are strongly associated with the definition of established mutational clusters in adult DLBCL. In our cohort, the morphological subtypes displayed different molecular profiles. IRF4 variants (some cases with 〉7 variants) and mutations in NF-kB pathway (CARD11, CD79B and MYD88-non L265P) were found specifically in the LBCL-IRF4 subgroup, whereas mutations in GCB related genes such as SOCS1 and EZH2 were particularly seen in cases with DLBCL diagnosis. All 49 patients with available follow-up received chemotherapy as first line treatment (41% containing Rituximab). Variables significantly associated with poor EFS in univariate analysis were age 〉18 years, ABC-COO, Stage IV, high genetic complexity (chromothripsis and/or 〉10 CN alterations), 2p16/REL gain/amplification, 9p21.3/CDKN2A homozygous deletions, MYC rearrangements and mutations in MYC, TP53 and DDX3X genes. CONCLUSION Despite pediatric/young-adult LBCL having overlapping features with adult disease our findings suggest that LBCL in young age have specific molecular mechanisms and highlight potential key drivers of these lymphomas in this age group. Disclosures No relevant conflicts of interest to declare.