The genomic and evolutionary landscape of osteosarcoma progression and lung metastasis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11029-11029 ◽  
Author(s):  
Jin Wang ◽  
Hua Bao ◽  
Huaiyuan Xu ◽  
Tony WH Shek ◽  
Xue Wu ◽  
...  
Keyword(s):  
Copy Number ◽  
Lung Metastases ◽  
Early Stage ◽  
Phylogenetic Analyses ◽  
Parallel Evolution ◽  
Genetic Alterations ◽  
Base Substitution ◽  
Primary Tumors ◽  
Whole Exome ◽  
First Time

11029 Background: Osteosarcoma (OS) is a primary malignant bone tumor that has a high potential to metastasize to lungs. Recent studies have characterized somatic mutations of primary OS tumors. Nevertheless, lung metastases of OS are poorly studied, and whether they harbor distinct genetic alterations beyond those observed in primary tumors is largely unknown. Methods: We performed whole-exome sequencing (WES) of matched primary tumors and lung metastases in a cohort of 15 OS patients. Somatic single nucleotide variations (SNV) and copy number alterations (CNA) were analyzed to characterize the genomic and evolutionary landscape of metastatic OS. Results: Compared to matched primary tumors, lung metastases exhibited higher transversion rate for base substitution, and poor overlap ( < 10%) of genetic alterations was observed between primary and metastasis tumors. Multiple novel significantly mutated genes were identified, including ZNF717 in lung metastases, SPDYE1 in primary tumors, and CRIPAK in both. Copy number analysis indicated recurrent CNAs, including NEURL1B deletion and FLG amplifications in lung metastases, GSTT1 deletion in primary tumors, and CEACAM gene family deletion in both. Furthermore, phylogenetic analyses revealed that paired primary tumors and metastases underwent parallel evolution with few ubiquitous clonal mutations, suggesting that OS metastases are likely to be derived from primary tumors at a very early stage of their evolution. Conclusions: This study for the first time provides important evidence that OS metastases harbor distinct genetic alterations compared with primary tumors. Our findings strongly support a parallel evolution model of primary and metastatic tumors. Moreover, several novel CNAs and significantly mutated genes that are specifically associated with lung metastases may provide future therapeutic insight for OS.

scholarly journals Breast Cancer Cell Re-Dissemination from Lung Metastases—A Mechanism for Enhancing Metastatic Burden

2021 ◽  
Vol 10 (11) ◽  
pp. 2340
Author(s):  
Lucia Borriello ◽  
John Condeelis ◽  
David Entenberg ◽  
Maja H. Oktay
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metastatic Disease ◽  
Breast Cancer Cells ◽  
Lung Metastases ◽  
Primary Tumors ◽  
Metastatic Burden ◽  
First Time ◽  
Do So

Although metastatic disease is the primary cause of mortality in cancer patients, the mechanisms leading to overwhelming metastatic burden are still incompletely understood. Metastases are the endpoint of a series of multi-step events involving cancer cell intravasation, dissemination to distant organs, and outgrowth to metastatic colonies. Here we show, for the first-time, that breast cancer cells do not solely disseminate to distant organs from primary tumors and metastatic nodules in the lymph nodes, but also do so from lung metastases. Thus, our findings indicate that metastatic dissemination could continue even after the removal of the primary tumor. Provided that the re-disseminated cancer cells initiate growth upon arrival to distant sites, cancer cell re-dissemination from metastatic foci could be one of the crucial mechanisms leading to overt metastases and patient demise. Therefore, the development of new therapeutic strategies to block cancer cell re-dissemination would be crucial to improving survival of patients with metastatic disease.

Religious Autonomy and Religious Entrepreneurship: An Evolutionary-Institutionalist’s Take on the Axial Age

2014 ◽  
Vol 13 (2) ◽  
pp. 105-134 ◽  
Author(s):  
Seth Abrutyn
Keyword(s):  
Early Stage ◽  
Parallel Evolution ◽  
Human History ◽  
Social Scientists ◽  
World Religions ◽  
Symbolic Space ◽  
Axial Age ◽  
The World ◽  
First Millennium ◽  
First Time

AbstractThrough the first millenniumbce, religio-cultural revolutions occurred in China, Greece, Israel, and India. Commonly referred to as the Axial Age, this epoch has been identified by some scholars as period of parallel evolution in which many of the World Religions appeared for the first time and humanity was forever changed. Axial scholarship, however, remains in an early stage as many social scientists and historians question the centrality of this era in the human story, while other unsettled debates revolve around what was common across each case. The paper below considers the Axial Age from an evolutionary-institutionalist’s perspective: what was axial was (1) the first successful religio-cultural entrepreneurs in human history and, thereby, (2) the evolution of autonomous religious spheres distinct from kinship and polity. Like the Urban Revolutions that qualitatively transformed human societies 3,000 years prior, the Axial Age represents a reconfiguration of the physical, temporal, social, and symbolic space in irreversible ways.

Comprehensive Genome-Wide Profile of Regional Gains and Losses in Multiple Myeloma Using Array-CGH: The 1q21 Amplification and Potential Role of the BCL-9 Gene in Multiple Myeloma Pathogenesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 785-785 ◽  
Author(s):  
Ruben Carrasco ◽  
Giovanni Tonon ◽  
Cameron Brennan ◽  
Alexei Protopopov ◽  
Raktim Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Copy Number ◽  
Structural Changes ◽  
Array Cgh ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Primary Tumors ◽  
Gains And Losses

Abstract Multiple Myeloma (MM) is characterized by a clonal proliferation of abnormal plasma cells in the bone marrow and is among the most frequent and lethal hematological diseases. In spite of significant effort towards the identification of the molecular events leading to this malignancy, the genetic alterations responsible for the pathogenesis of this disease remain poorly understood. Regional copy number alterations (CNAs) in cancer genomes have been among the most informative structural changes in cancer and have led to the discovery of many oncogenes and tumor supressor genes. Using array comparative genomic hybridization (array-CGH) and expression microarray technologies we have analyzed a large collection of cell lines and clinically annotated primary tumors. This high-resolution genomic analysis has identified all previously reported regional gains and losses as well as many novel highly recurrent genetic loci with potential biological and clinical relevance. In particular, we have identified an amplification at chromosome 1q21 as one of the most recurrent genetic changes in cell lines and in a subgroup of primary tumors. This chromosomal change has been previously implicated with disease progression. Analysis across several cell lines has allowed the identification of a Minimal Common Region (MCRs) of amplification at 1q21. Correlation between DNA copy number changes and expression profiling data has identified a limited set of candidate genes within this MCR that are amplified and overexpressed. Using shRNAi technology we have identified BCL-9 as a candidate gene residing at the 1q21 MCR. In vitro and in vivo functional data about the role of BL-9 will be presented. These data will provide critical understanding on the diverse pathways leading to Multiple Myeloma progression.

An Atlas of the MicroRNA Genome in Human DLBCL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 563-563
Author(s):  
Shailaja Karanti ◽  
Aswani Bolla ◽  
Ciara Dillon ◽  
Ryan S. Robetorye ◽  
Ricardo C.T. Aguiar
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Copy Number ◽  
Genetic Material ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Structural Defects ◽  
Mirna Biogenesis ◽  
Primary Tumors ◽  
Mirna Genes

Abstract MicroRNAs (miRNA) preferentially map to unstable chromosomal regions suggesting that structural defects may contribute to their role in cancer. Diffuse large B-cell lymphoma (DLBCL) is characterized by recurring chromosomal translocations and DNA imbalances, but the integrity of the miRNA genome in this neoplasm is unknown. To address this issue at a genome-wide level we designed a novel oligonucleotide-based array-CGH platform (Agilent) that covers at high density (∼500bp interval) the loci for 471 human miRNAs and 17 genes involved in miRNA biogenesis. We used this platform to analyze the miRNA genes of a collection of 87 well-characterized DLBCLs, including 60 primary tumors and 27 DLBCL cell lines. We found widespread disruption of miRNA genes in these lymphomas with 57 of the 60 primary tumors (95%) and 100% of the cell lines exhibiting alteration of at least one miRNA locus. Only 8 miRNA loci were intact in all samples. Most of the tumors had multiple miRNA loci disrupted, a phenomenon reminiscent of the multiple and cooperative aberrations of classical mRNA genes in cancer. The majority of the frequently disrupted miRNAs exhibited gains rather than loss of genetic material. A total of 48 miRNAs (representing 21 independent miRNA clusters) showed gains of genetic material in more than 20% of the cases, whereas only seven miRNA genes had loss of material in a significant percentage of the tumors. The five miRNA loci that most frequently exhibited DNA gain included miR-511-1, miR-339, miR-1-1, miR-133a-2 and miR-589, and the miRNA genes that most commonly exhibited loss of material were miR-31, miR-548a-2, miR-491, and the miR-15a/miR-16 cluster. In contrast, the genes involved in miRNA biogenesis were highly stable and only AGO2, DGCR8-Pasha and FMR1 were disrupted in more 10% of the cases. There was significant overlap between the aberrations found in primary tumors and DLBCL cell lines, especially concerning the miRNAs targeted for deletion. An examination of eight miRNAs previously found to be expressed and/or play a role in B-cell biology (miRs 142, 144, 150, 155, 223, 26a, 191 and 16) revealed that most of these genes exhibited frequent gains of genetic material, with the exception of a highly stable miR-155 locus and the miR-16 locus on chromosome 13q, which showed loss of genetic material in ∼30% of the cases. These data indicated that the well known over-expression of miR-155 in DLBCL is not linked to copy number changes and suggested that genomic instability may lead to abnormal expression of the other B-cell relevant miRNAs. To test this hypothesis we determined the expression of miR-26a and miR-16, the two B-cell relevant miRNAs with the highest frequency of genetic alterations, using a real-time quantitative RT-PCR assay that specifically amplifies the mature miRNA. Surprisingly, there was no significant difference in the expression of miR-16 in tumors or cell lines with or without deletion of genetic material at this locus, suggesting that this miRNA may not play a role in DLBCL. In contrast, miR-26a expression correlated well with its copy number and was ∼3.5 higher in tumors (p< 0.01) and cell lines (p=0.02) with DNA gain than in those with an intact genomic locus. These data suggest that mirR-26a, which is predicted to modulate PTEN expression, may act as an oncogene in DLBCL. In summary, our high resolution analysis creates a map of miRNA integrity in DLBCL, a critical tool to start to delineate their role in this tumor.

scholarly journals The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA

2021 ◽  
Vol 5 (7) ◽  
pp. 1991-2002
Author(s):  
Lieselot Buedts ◽  
Iwona Wlodarska ◽  
Julio Finalet-Ferreiro ◽  
Olivier Gheysens ◽  
Luc Dehaspe ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Copy Number ◽  
Early Stage ◽  
Read Depth ◽  
Metabolic Tumor Volume ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Classical Hodgkin Lymphoma ◽  
Cell Free Dna ◽  
Free Dna

Abstract The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.

scholarly journals Paired comparisons of mutational profiles before and after brachytherapy in asian uveal melanoma patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Woo Seung Lee ◽  
Junwon Lee ◽  
Jun Jeong Choi ◽  
Hyun Goo Kang ◽  
Sung Chul Lee ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Statistical Significance ◽  
Paired Comparisons ◽  
Copy Number Alterations ◽  
Primary Tumors ◽  
Molecular Features ◽  
Whole Exome ◽  
Before And After ◽  
Melanoma Patients ◽  
First Time

AbstractUveal melanoma(UM) is the most common primary intraocular malignancy in adults. However, the incidence of UM in Asia is 10 to 20 times less than in Western populations. Therefore, for the first time, we report our whole exome sequencing (WES) data analysis to discover differences in the molecular features of Asian and Western UM, and to determine the disparities between the primary tumor before brachytherapy and enucleated samples after brachytherapy. WES of 19 samples (13 primary tumors, 5 enucleation samples after brachytherapy, and 1 liver metastasis) from 13 patients diagnosed with UM and treated between 2007 and 2019 at the Yonsei University Health System (YUHS) were analyzed using bioinformatics pipelines. We identified significantly altered genes in Asian UM and changes in mutational profiles before and after brachytherapy using various algorithms. GNAQ, BAP1, GNA11, SF3B1 and CYSLTR2 were significantly mutated in Asian UM, which is similar that reported frequently in previous Western-based UM studies. There were also similar copy number alterations (M3, 1p loss, 6p gain, 8q gain) in both groups. In paired comparisons of the same patients, DICER1 and LRP1B were distinctly mutated only in tumor samples obtained after brachytherapy using rare-variant association tests (P = 0.01, 0.01, respectively). The mutational profiles of Asian UM were generally similar to the data from previous Western-based studies. DICER1 and LRP1B were newly mutated genes with statistical significance in the regrowth samples after brachytherapy compared to the primary tumors, which may be related to resistance to brachytherapy.

scholarly journals Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5984
Author(s):  
Orsolya Papp ◽  
Viktória Doma ◽  
Jeovanis Gil ◽  
György Markó-Varga ◽  
Sarolta Kárpáti ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Copy Number ◽  
Lung Metastases ◽  
Ectopic Expression ◽  
Gene Copy Number ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Primary Tumors ◽  
Specific Manner ◽  
Organ Specific

Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays (N = 38 samples) to reveal organ specific alterations. Results were partly completed by proteomic analysis. A significant increase of high-copy number gains was found in an organ-specific manner, whereas copy number losses were predominant in brain metastases, including the loss of numerous DNA damage response genes. Amplification of many immune genes was also observed, several of them are novel in melanoma, suggesting that their ectopic expression is possibly underestimated. This “immunogenic mimicry” was exclusive for lung metastasis. We also provided evidence for the possible autocrine activation of c-MET, especially in brain and lung metastases. Furthermore, frequent loss of 9p21 locus in brain metastases may predict higher metastatic potential to this organ. Finally, a significant correlation was observed between BRAF gene copy number and mutant allele frequency, mainly in lung metastases. All of these events may influence therapy efficacy in an organ specific manner, which knowledge may help in alleviating difficulties caused by resistance.

Whole Exome Sequencing Reveals Clonal Evolution Pattern and Driver Mutations Of Relapsed Pediatric AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1410-1410
Author(s):  
Kenichi Yoshida ◽  
Norio Shiba ◽  
Yuichi Shiraishi ◽  
Akira Shimada ◽  
Kiminori Terui ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Copy Number ◽  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Driver Mutations ◽  
Pediatric Leukemia ◽  
Term Survival ◽  
Whole Exome ◽  
Pediatric Aml

Abstract Background Pediatric acute myeloid leukemia (AML) comprises ∼20% of pediatric leukemia, representing one of the major therapeutic challenges in pediatric oncology. Nearly 40% of patients still relapse after present first-line therapies and once the relapse occurs, the long-term survival rates decrease, ranging from 21% to 34%. As for the pathogenesis of AML relapse, the recent development of massively parallel sequencing technologies has provided a new opportunity to investigate comprehensive genetic alterations that are involved in tumor recurrence of adult AML. However, little is known about the molecular details of relapsed pediatric AML. Methods In order to reveal the clonal origin and the major mutational events in relapsed pediatric AML, we performed whole exome sequencing of 4 trio samples from diagnostic, relapsed and complete remission phases using Illumina HiSeq 2000. Copy number abnormalities were also detected using whole exome sequencing. Subsequently, deep sequencing of identified mutations was performed to evaluate intra-tumor heterogeneity and the clonolocal history of relapsed clones. Results Whole-exome sequencing of 12 samples from 4 patients were analyzed with a mean coverage of more than x100, and 95 % of the targeted sequences were analyzed at more than x20 depth on average. A total of 98 somatic mutations were identified, where mean number of non-silent mutations was higher at relapsed phase than at the time of diagnosis (14.0/case vs 10.5/case) (p=0.270). Assessment of clonality using variant allele frequencies of individual mutations suggested that some mutations were subclonal mutations, consisting of intra-tumor heterogeneity both at the time of diagnosis and at relapse. In all 4 patients, relapsed AML evolved from one of the subclones at the initial phase, which was accompanied by many additional mutations including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process of leukemia recurrence. Forty-six out of the 98 mutations were specific either at the time of diagnosis (n = 16) or at relapse (n = 30). Relapse-specific mutations and copy number changes were found in several genes including known drivers such as NRAS and CREBBP. These mutations were further investigated in an extended cohort of relapsed pediatric AML samples using targeted sequencing to evaluate their prevalence. In some cases, AML relapse may accompany a dynamic clonal change. For example, some bona fide driver mutations, such as KRAS mutations, that were predominant at the time of diagnosis disappeared in relapsed samples. Discussion Whole exome sequencing unmasked clonal structure of primary and relapsed pediatric AML, which helped to understand the underlying mechanism of relapse in pediatric AML. Our results suggested that pediatric AML has intra-tumor heterogeneity and subclonal mutations such as NRAS and CREBBP occurring in one of the subclones could drive the AML relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Whole Exome and Transcriptome Sequencing in 1042 Cases Reveals Distinct Clinically Relevant Genetic Subgroups of Follicular Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 19-19
Author(s):  
Xiang Li ◽  
Rachel Kositsky ◽  
Anupama Reddy ◽  
Cassandra Love ◽  
Kikkeri Naresh ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Copy Number ◽  
Research Funding ◽  
Genetic Alterations ◽  
Advisory Committees ◽  
Dna And Rna ◽  
Whole Exome ◽  
Grade 3

Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

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