{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"dataset_type":["Illumina Genome Analyzer II;, Illumina Genome Analyzer IIx"],"full_dataset_link":["https://ega-archive.org/datasets/EGAD00001000083"],"sample_count":["61"],"description":["EGA dataset EGAD00001000083"],"repository":["EGA"],"title":["Recurrent Somatic Mutations in CLL"],"pubmed_abstract":["Here we perform whole-exome sequencing of samples from 105 individuals with chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults in Western countries. We found 1,246 somatic mutations potentially affecting gene function and identified 78 genes with predicted functional alterations in more than one tumor sample. Among these genes, SF3B1, encoding a subunit of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), is somatically mutated in 9.7% of affected individuals. Further analysis in 279 individuals with CLL showed that SF3B1 mutations were associated with faster disease progression and poor overall survival. This work provides the first comprehensive catalog of somatic mutations in CLL with relevant clinical correlates and defines a large set of new genes that may drive the development of this common form of leukemia. The results reinforce the idea that targeting several well-known genetic pathways, including mRNA splicing, could be useful in the treatment of CLL and other malignancies.","Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.","Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes-most of which are not differentially expressed-exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences."],"pubmed_title":["Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.","Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.","Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia."],"pubmed_authors":["Puente Xose S XS, Pinyol Magda M, Quesada Víctor V, Conde Laura L, Ordóñez Gonzalo R GR, Villamor Neus N, Escaramis Georgia G, Jares Pedro P, Beà Sílvia S, González-Díaz Marcos M, Bassaganyas Laia L, Baumann Tycho T, Juan Manel M, López-Guerra Mónica M, Colomer Dolors D, Tubío José M C JM, López Cristina C, Navarro Alba A, Tornador Cristian C, Aymerich Marta M, Rozman María M, Hernández Jesús M JM, Puente Diana A DA, Freije José M P JM, Velasco Gloria G, Gutiérrez-Fernández Ana A, Costa Dolors D, Carrió Anna A, Guijarro Sara S, Enjuanes Anna A, Hernández Lluís L, Yagüe Jordi J, Nicolás Pilar P, Romeo-Casabona Carlos M CM, Himmelbauer Heinz H, Castillo Ester E, Dohm Juliane C JC, de Sanjosé Silvia S, Piris Miguel A MA, de Alava Enrique E, San Miguel Jesús J, Royo Romina R, Gelpí Josep L JL, Torrents David D, Orozco Modesto M, Pisano David G DG, Valencia Alfonso A, Guigó Roderic R, Bayés Mónica M, Heath Simon S, Gut Marta M, Klatt Peter P, Marshall John J, Raine Keiran K, Stebbings Lucy A LA, Futreal P Andrew PA, Stratton Michael R MR, Campbell Peter J PJ, Gut Ivo I, López-Guillermo Armando A, Estivill Xavier X, Montserrat Emili E, López-Otín Carlos C, Campo Elías E","Quesada Víctor V, Conde Laura L, Villamor Neus N, Ordóñez Gonzalo R GR, Jares Pedro P, Bassaganyas Laia L, Ramsay Andrew J AJ, Beà Sílvia S, Pinyol Magda M, Martínez-Trillos Alejandra A, López-Guerra Mónica M, Colomer Dolors D, Navarro Alba A, Baumann Tycho T, Aymerich Marta M, Rozman María M, Delgado Julio J, Giné Eva E, Hernández Jesús M JM, González-Díaz Marcos M, Puente Diana A DA, Velasco Gloria G, Freije José M P JM, Tubío José M C JM, Royo Romina R, Gelpí Josep L JL, Orozco Modesto M, Pisano David G DG, Zamora Jorge J, Vázquez Miguel M, Valencia Alfonso A, Himmelbauer Heinz H, Bayés Mónica M, Heath Simon S, Gut Marta M, Gut Ivo I, Estivill Xavier X, López-Guillermo Armando A, Puente Xose S XS, Campo Elías E, López-Otín Carlos C","Ferreira Pedro G PG, Jares Pedro P, Rico Daniel D, Gómez-López Gonzalo G, Martínez-Trillos Alejandra A, Villamor Neus N, Ecker Simone S, González-Pérez Abel A, Knowles David G DG, Monlong Jean J, Johnson Rory R, Quesada Victor V, Djebali Sarah S, Papasaikas Panagiotis P, López-Guerra Mónica M, Colomer Dolors D, Royo Cristina C, Cazorla Maite M, Pinyol Magda M, Clot Guillem G, Aymerich Marta M, Rozman Maria M, Kulis Marta M, Tamborero David D, Gouin Anaïs A, Blanc Julie J, Gut Marta M, Gut Ivo I, Puente Xose S XS, Pisano David G DG, Martin-Subero José Ignacio JI, López-Bigas Nuria N, López-Guillermo Armando A, Valencia Alfonso A, López-Otín Carlos C, Campo Elías E, Guigó Roderic R"],"additional_accession":[]},"is_claimable":false,"name":"EGAS00000000092-ega-13012012 - samples","description":"Recurrent Somatic Mutations in CLL","dates":{"updated":"2019-10-31 12:52:09"},"accession":"EGAD00001000083","cross_references":{"TAXONOMY":["9606"],"pubmed":["24265505","21642962","22158541"],"EGA":["EGAC00001000010","EGAS00000000092","EGAS00001000374"]}}