EGAGenomicsIllumina HiSeq 2000Otherhttps://ega-archive.org/studies/EGAS00001000534EGAEGA study EGAS00001000534WGBS of cell typesRNA-seq CLL450K_DKFZ_CLL_NBrestrictedEGAAlthough clonal selection by genetic driver aberrations in cancer is well documented, the ability of epigenetic alterations to promote tumor evolution is undefined. We used 450k arrays and next-generation sequencing to evaluate intratumor heterogeneity and evolution of DNA methylation and genetic aberrations in chronic lymphocytic leukemia (CLL). CLL cases exhibit vast interpatient differences in intratumor methylation heterogeneity, with genetically clonal cases maintaining low methylation heterogeneity and up to 10% of total CpGs in a monoallelically methylated state. Increasing methylation heterogeneity correlates with advanced genetic subclonal complexity. Selection of novel DNA methylation patterns is observed only in cases that undergo genetic evolution, and independent genetic evolution is uncommon and is restricted to low-risk alterations. These results reveal that although evolution of DNA methylation occurs in high-risk, clinically progressive cases, positive selection of novel methylation patterns entails coevolution of genetic alteration(s) in CLL.Evolution of DNA methylation is linked to genetic aberrations in chronic lymphocytic leukemia.Oakes Christopher C CC, Claus Rainer R, Gu Lei L, Assenov Yassen Y, Hüllein Jennifer J, Zucknick Manuela M, Bieg Matthias M, Brocks David D, Bogatyrova Olga O, Schmidt Christopher R CR, Rassenti Laura L, Kipps Thomas J TJ, Mertens Daniel D, Lichter Peter P, Döhner Hartmut H, Stilgenbauer Stephan S, Byrd John C JC, Zenz Thorsten T, Plass Christoph CLymphoplasmacytoid Lymphomas, CLL Lymphoplasmacytoid Lymphomas, CLL, B Cells, Chronic B-Cell Leukemia, Chronic B-Cell, determination, Lymphocytic Leukemia, Bursa-Dependent Lymphocytes, B-Lymphocytic Leukemias, chronic LYMPHOCYTIC, Chronic B-Lymphocytic, B-Cell, Lymphatic Leukemia, DNA Methylations, B-cell chronic lymphocytic leukaemia, B Cell, Small, B-cell chronic lymphoid leukemia, Chronic B-Cell Leukemias, Well-Differentiated Lymphocytic, Lymphoplasmacytoid Lymphoma, Well Differentiated, Chronic Lymphocytic Leukemias, Lymphomas, chronic lymphatic, Low-Grade, average, Lymphocytic, B-cell, Leukemia, DNA methylation maintenance, B-cell chronic lymphocytic leukemia, Malignancy, Small-Cell Lymphomas, CLL Lymphoplasmacytoid Lymphoma, Plasmacytoid, Small Lymphocytic Lymphoma, Well-Differentiated Lymphocytic Lymphoma, DNA methylation, Small-Cell Lymphoma, B-Lymphocytic Leukemia, B Cell., Diffuse, Lymphoblastic Leukemias, Chronic Lymphatic Leukemias, B lymphocyte, Disrupted In B Cell Malignancy, Chronic, Diffuse Well Differentiated Lymphocytic Lymphoma, Malignancies, Chronic B-Lymphocytic Leukemias, chronic lymphatic leukaemia, Chronic Lymphocytic, Diffuse Well-Differentiated Lymphocytic Lymphoma, Low Grade, Methylations, leukemia, B-Cell Chronic Lymphocytic Leukemia, B Lymphocytes, B Cell Malignancy, Small Cell, 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, 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, Lymphatic Leukemias, Lymphocytic Lymphomas, Well-Differentiated Lymphocytic Lymphomas, B-Cell Leukemias, Disrupted In B-Cell Malignancy, Lymphoblastic, Chronic Lymphoblastic, Bursa-Equivalent Lymphocyte, Small Lymphocytic, Chronic Lymphoblastic Leukemias, Low-Grade B-Cell Malignancy, Small-Cell, Lymphocytic Lymphoma, B-Lymphocyte, Lymphoplasmacytoid, CLL Lymphoplasmacytoid, Lymphoma, chronic lymphocytic leukaemia, assay, DNA, B-lymphocyte, Methylation, Small Lymphocytic LymphomasHSPABP2, H2S(D2S), CLL, Cll, other disease, B Cells, degree (angle), DNS, Activity, (Deoxyribonucleotide)n, Laboratory, Bursa-Dependent Lymphocytes, Neoplasms, 2210017D18Rik, dCHIP, Benign Neoplasm, B cell, chronic LYMPHOCYTIC, Gene, SCAR16, broad, Tumor, Malignant, B-cell chronic lymphocytic leukaemia, Deoxyribonucleic acids, cll, CML, DmelCG5203, Deoxyribonucleic Acid, diseases, B-cell chronic lymphoid leukemia, disease or disorder, diseases and disorders, Research Activity, Laboratory Research, 2310040B03Rik, chronic lymphatic, Priorities, average, study, B-cell, functional differentiation, thymus nucleic acid, human disease, NY-CO-7, Gene Expressions, pattern, B-cell chronic lymphocytic leukemia, Malignancy, Genomes, Research, distribution, Chip, ChIP, Tissue, CHIP, bisulfite, Double Stranded, TF binding, Deoxyribonucleic acid, Expressions, adult chronic leukaemia, Epigenomic, Ect5, genetic, non-neoplastic, Neoplasias, chip, B lymphocyte, malignant neoplasm, Clients, heterogeneity, DmelCG3924, adult chronic leukemia, AW046544, disorder, s, Homo sapiens disease, Malignancies, Double-Stranded DNA, Development and Research, Expression, (Deoxyribonucleotide)m, Research Priority, UBOX1, deoxyribonucleic acids, chronic lymphatic leukaemia, DNAn, 0610033N24Rik, constitutitional genetic, PP1131, CG7937, Cancer, Tumors, leukemia, l(2)k04405, Malignant Neoplasm, wide/broad, bead, hydrosulfite, B Lymphocytes, DNAn+1, transcription regulator binding, Chronic Lymphocytic Leukemia, familial, disorders, lymphoplasmacytic leukaemia, CG5203, 311, Research Priorities, medical condition, Double-Stranded, l(2)04405, Client, lymphoplasmacytic leukemia, chronic, (Deoxyribonucleotide)n+m, Priority, Benign, MT, 93Bal, Research Activities, Diseases, Neoplasm, condition, simple tissue, chronic lymphatic leukemia, lymphocytic, ds-DNA, desoxyribose nucleic acid, SDCCAG7, Research and Development, small lymphocytic lymphoma, primary cancer, c15, dLdb, Epigenetic, Ldb, LDB, DmelCG7937, Benign Neoplasms, Chromatin Immunoprecipitation, Bursa-Equivalent Lymphocyte, Cancers, whole genome, arc degree, CG3924, malignant tumor, Malignant Neoplasms, Activities, disease, wide, Hox11-311, dLDB/Chip, Patient, B-Lymphocyte, ds DNA, Desoxyribonukleinsaeure, chronic lymphocytic leukaemia, inherited genetic, DNA, Epigenetics, B-lymphocyte, other neoplasm, hereditary, Neoplasia, Malignant Neoplasms.Lymphoplasmacytoid Lymphomas, CLL Lymphoplasmacytoid Lymphomas, CLL, Chronic B-Cell Leukemia, Chronic B-Cell, Lymphocytic Leukemia, B-Lymphocytic Leukemias, chronic LYMPHOCYTIC, Chronic B-Lymphocytic, B-Cell, Lymphatic Leukemia, DNA Methylations, B-cell chronic lymphocytic leukaemia, B Cell, Small, B-cell chronic lymphoid leukemia, Chronic B-Cell Leukemias, Well-Differentiated Lymphocytic, Lymphoplasmacytoid Lymphoma, Well Differentiated, Chronic Lymphocytic Leukemias, Lymphomas, chronic lymphatic, Low-Grade, Lymphocytic, Leukemia, DNA methylation maintenance, B-cell chronic lymphocytic leukemia, Malignancy, Small-Cell Lymphomas, CLL Lymphoplasmacytoid Lymphoma, Plasmacytoid, Small Lymphocytic Lymphoma, Well-Differentiated Lymphocytic Lymphoma, DNA methylation, Small-Cell Lymphoma, B-Lymphocytic Leukemia, B Cell., genetic, Diffuse, Lymphoblastic Leukemias, Chronic Lymphatic Leukemias, Disrupted In B Cell Malignancy, Chronic, Diffuse Well Differentiated Lymphocytic Lymphoma, Malignancies, Chronic B-Lymphocytic Leukemias, chronic lymphatic leukaemia, Chronic Lymphocytic, constitutitional genetic, Diffuse Well-Differentiated Lymphocytic Lymphoma, Low Grade, Methylations, leukemia, B-Cell Chronic Lymphocytic Leukemia, B Cell Malignancy, Small Cell, familial, 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, Well-Differentiated, Chronic Lymphatic, Small Cell Lymphoma, 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, 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, chronic lymphocytic leukaemia, inherited genetic, DNA, hereditary, Methylation, Small Lymphocytic Lymphomasleukemia, CLL, Cll, Malignant Neoplasm, cou, selection process, Neoplasms, familial, Benign Neoplasm, Chronic Lymphocytic Leukemia, chronic LYMPHOCYTIC, lymphoplasmacytic leukaemia, 311, DNA Methylations, Tumor, Tl3, Malignant, Tl2, lymphoplasmacytic leukemia, chronic, B-cell chronic lymphocytic leukaemia, results, cll, Relative, CML, Lr, MT, Benign, 93Bal, B-cell chronic lymphoid leukemia, Relative Risks, Neoplasm, chronic lymphatic leukemia, Low, methylation, lymphocytic, chronic lymphatic, Relative Risk, small lymphocytic lymphoma, primary cancer, me75, c15, DNA methylation maintenance, Exhibit, B-cell chronic lymphocytic leukemia, Risk, Malignancy, Epigenetic, DmelCG7937, CG7937., Risks, Benign Neoplasms, Cancers, DNA methylation, malignant tumor, adult chronic leukaemia, D17Mit170, T1, Epigenomic, Malignant Neoplasms, Ect5, genetic, Neoplasias, Hox11-311, malignant neoplasm, heterogeneity, adult chronic leukemia, Bra, chronic lymphocytic leukaemia, inherited genetic, Malignancies, DNA, chronic lymphatic leukaemia, Epigenetics, constitutitional genetic, other neoplasm, hereditary, Methylations, Neoplasia, Methylation, CG7937, Cancer, TumorsfalseAnalysis of DNA methylation in normal B cells and chronic lymphocytic leukemiaCharting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. As second study using these samples focued on evolution and resulting intra-tumor heterogeneity in CLL. We used 450k bead-chip arrays to study DNA methylomes in 68 chronic lymphocytic leukemia (CLL) cases, including 28 serial cases. The result establishs linked evolution of epigenetic and genetic alterations in progressive disease, revealing an important aspect of the biology of epigenetics in cancer.2017-07-26 15:39:26EGAS00001000534960624356097EGAD00010000871EGAD00001001676EGAD00001001675EGAC00001000279