EGAGenomicsExome Sequencing; Tumor vs. Matched-NormaldbGaPEGA study phs000364.v1.p1http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000364.v1.p1dbGaPEGArestrictedhttps://ega-archive.org/studies/phs000364.v1.p1The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ∼30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome.Fabbri Giulia G, Rasi Silvia S, Rossi Davide D, Trifonov Vladimir V, Khiabanian Hossein H, Ma Jing J, Grunn Adina A, Fangazio Marco M, Capello Daniela D, Monti Sara S, Cresta Stefania S, Gargiulo Ernesto E, Forconi Francesco F, Guarini Anna A, Arcaini Luca L, Paulli Marco M, Laurenti Luca L, Larocca Luigi M LM, Marasca Roberto R, Gattei Valter V, Oscier David D, Bertoni Francesco F, Mullighan Charles G CG, Foá Robin R, Pasqualucci Laura L, Rabadan Raul R, Dalla-Favera Riccardo R, Gaidano Gianluca GFabbri Giulia G, Khiabanian Hossein H, Holmes Antony B AB, Wang Jiguang J, Messina Monica M, Mullighan Charles G CG, Pasqualucci Laura L, Rabadan Raul R, Dalla-Favera Riccardo RLymphoplasmacytoid Lymphomas, CLL Lymphoplasmacytoid Lymphomas, CLL, Chronic B-Cell Leukemia, Chronic B-Cell, determination, Lymphocytic Leukemia, Complete Exome, B-Lymphocytic Leukemias, number, chronic LYMPHOCYTIC, Chronic B-Lymphocytic, B-Cell, Lymphatic Leukemia, presence, B-cell chronic lymphocytic leukaemia, B Cell, Small, B-cell chronic lymphoid leukemia, Whole Transcriptome, Transcriptome Sequencing, Chronic B-Cell Leukemias, Well-Differentiated Lymphocytic, Lymphoplasmacytoid Lymphoma, Well Differentiated, Chronic Lymphocytic Leukemias, Lymphomas, chronic lymphatic, Low-Grade, Lymphocytic, WES, Complete, Leukemia, Exome Sequencings, B-cell chronic lymphocytic leukemia, Malignancy, Small-Cell Lymphomas, Complete Exome Sequencing, Whole Transcriptome Sequencing, CLL Lymphoplasmacytoid Lymphoma, Plasmacytoid, Small Lymphocytic Lymphoma, Well-Differentiated Lymphocytic Lymphoma, Small-Cell Lymphoma, B-Lymphocytic Leukemia, B Cell., Sequencing, Diffuse, Lymphoblastic Leukemias, Whole Exome, Chronic Lymphatic Leukemias, Disrupted In B Cell Malignancy, Whole, high density, Chronic, Diffuse Well Differentiated Lymphocytic Lymphoma, Malignancies, Chronic B-Lymphocytic Leukemias, chronic lymphatic leukaemia, Chronic Lymphocytic, Diffuse Well-Differentiated Lymphocytic Lymphoma, Low Grade, leukemia, B-Cell Chronic Lymphocytic Leukemia, Complete Exome Sequencings, B Cell Malignancy, Small Cell, Exome, Chronic Lymphocytic Leukemia, Chronic B-Lymphocytic Leukemia, lymphoplasmacytic leukaemia, B-Cell Malignancy, Low-Grade B-Cell Malignancies, Chronic Lymphoblastic Leukemia, lymphoplasmacytic leukemia, Leukemias, chronic, B-Cell Leukemia, count in organism, Exome Sequencing, Well-Differentiated, Chronic Lymphatic, Small Cell Lymphoma, chemical analysis, Lymphocytic Leukemias, B-Cell Malignancies, B Lymphocytic Leukemia, B Cell Chronic Lymphocytic Leukemia, chronic lymphatic leukemia, B Cell Leukemia, lymphocytic, Low-Grade B-Cell, Lymphoblastic Leukemia, Chronic Lymphatic Leukemia, small lymphocytic lymphoma, Complete Transcriptome, Complete Transcriptome Sequencing, Lymphatic Leukemias, Lymphocytic Lymphomas, Well-Differentiated Lymphocytic Lymphomas, B-Cell Leukemias, Disrupted In B-Cell Malignancy, Lymphoblastic, Chronic Lymphoblastic, Small Lymphocytic, Chronic Lymphoblastic Leukemias, Low-Grade B-Cell Malignancy, Small-Cell, Lymphocytic Lymphoma, Lymphoplasmacytoid, CLL Lymphoplasmacytoid, Lymphoma, cardinality, Whole Exome Sequencing, chronic lymphocytic leukaemia, assay, Transcriptome Sequencings, Small Lymphocytic Lymphomasbig, Forms, CLL, Cll, other disease, Antemortem Diagnosis, Materials, xnotch, Richter's transformation, determination, hN1, full spectrum, regulation by symbiont of host system process, low frequency, number, positive regulation by symbiont of host non-apoptotic programmed cell death, chronic LYMPHOCYTIC, Gene, Diagnosis, presence, B-cell chronic lymphocytic leukaemia, brl, Mutations, cll, CML, large, DmelCG4114, NOTCH, diseases, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, B-cell chronic lymphoid leukemia, Q1 spectrum, Associations, leukaemia NOS, Mass, symptoms, Clinical Progression, pathogenesis, Screening, disease or disorder, diseases and disorders, Leucocythaemia, Antemortem, leukaemia, notch, adult, chronic lymphatic, Genomes., Progression, human disease, Genetic, Clinical, stimulation by symbiont of host programmed cell death, B-cell chronic lymphocytic leukemia, Genomes, occurrence, prevalence, Leucocythemias, causes, Diagnoses and Examinations, Richter syndrome, adult chronic leukaemia, Q3 spectrum, Ect5, genetic, non-neoplastic, notch1-a, Clinical Course, time of survival, great, Xotch, causality, adult chronic leukemia, Exacerbation, disorder, Homo sapiens disease, T14, chronic lymphatic leukaemia, constitutitional genetic, CG7937, Diagnose, incidence, infrequent, leukemia, Antemortem Diagnoses, screening, Disease, activation by organism of non-apoptotic programmed cell death in other organism, findings, hemolysin activity, frequency, familial, Chronic Lymphocytic Leukemia, CG4114, Disease Exacerbation, disorders, lymphoplasmacytic leukaemia, 311, 9930111A19Rik, medical condition, lin-12, Cistrons, lymphoplasmacytic leukemia, chronic, Leukemias, Examination and Diagnoses, results, Expanded, Diagnoses, Richter transformation, N1, count in organism, Motch, Postmortem, Screenings, survival, 93Bal, Mass Screenings, 1270, Examinations and Diagnoses, chemical analysis, Diseases, modulation by symbiont of host system process, Genetic Materials, condition, chronic lymphatic leukemia, lymphocytic, Postmortem Diagnosis, Adults, outbreaks, Genetic Material, activation, Leucocythaemias, Diagnoses and Examination, xnotch1, small lymphocytic lymphoma, Leucocythemia, Single-Stage Mass Spectrometry, Postmortem Diagnoses, c15, death rate, DmelCG7937, expanded, Ex, signs, common, INSDC_feature:gene, whole genome, surveillance, morbidity, endemics, l(2)01270, disease, Hox11-311, Richter's syndrome, enlarged, Material, AOVD1, activation by symbiont of host programmed cell death, cardinality, AOS5, l(2)ey, chronic lymphocytic leukaemia, Cistron, epidemics, inherited genetic, notch-1, assay, TAN1, Tan1, hereditary, Mis6Lymphoplasmacytoid Lymphomas, CLL Lymphoplasmacytoid Lymphomas, CLL, Chronic B-Cell Leukemia, Chronic B-Cell, xnotch, determination, Lymphocytic Leukemia, hN1, B-Lymphocytic Leukemias, chronic LYMPHOCYTIC, Chronic B-Lymphocytic, B-Cell, Lymphatic Leukemia, B-cell chronic lymphocytic leukaemia, B Cell, Small, NOTCH, Roles, B-cell chronic lymphoid leukemia, Concepts, Chronic B-Cell Leukemias, Well-Differentiated Lymphocytic, Lymphoplasmacytoid Lymphoma, Well Differentiated, Chronic Lymphocytic Leukemias, Lymphomas, notch, chronic lymphatic, Low-Grade, Lymphocytic, Leukemia, B-cell chronic lymphocytic leukemia, Malignancy, Genomes, Small-Cell Lymphomas, CLL Lymphoplasmacytoid 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AOVD1, cardinality, High Throughput Nucleotide Sequencing, epidemics, Treatment, assay, hereditary, Ion Proton, High-Throughput NucleotidefalseHigh density copy number analysis and whole exome sequencing of chronic lymphocytic leukemia<p>The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.</p>
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