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Article

Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia

Publicated to:Nature Genetics. 44 (1): 47-52 - 2012-01-01 44(1), DOI: 10.1038/ng.1032

Authors: Quesada, Victor; Conde, Laura; Villamor, Neus; Ordonez, Gonzalo R; Jares, Pedro; Bassaganyas, Laia; Ramsay, Andrew J; Bea, Silvia; Pinyol, Magda; Lopez-Guerra, Monica; Colomer, Dolors; Navarro, Alba; Baumann, Tycho; Aymerich, Marta; Rozman, Maria; Delgado, Julio; Gine, Eva; Hernandez, Jesus M; Gonzalez-Diaz, Marcos; Puente, Diana A; Velasco, Gloria; Freije, Jose M P; Tubio, Jose M C; Royo, Romina; Gelpi, Josep L; Orozco, Modesto; Pisano, David G; Zamora, Jorge; Vazquez, Miguel; Valencia, Alfonso; Himmelbauer, Heinz; Bayes, Monica; Heath, Simon; Gut, Marta; Gut, Ivo; Estivill, Xavier; Puente, Xose S; Campo, Elias; Lopez-Otin, Carlos

Affiliations

Centro de Regulación Genómica - Author
Centro Nacional de Investigaciones Oncológicas - Author
Hospital Clinic Barcelona - Author
Hospital Universitario de Salamanca - Author
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS - Author
Instituto Universitario de Oncologia del Principado de Asturias - Author
Universitat de Barcelona - Author
Universitat Pompeu Fabra - Author
‎ CRG UPF, Ultrasequencing Unit, Barcelona, Spain - Author
‎ Ctr Nacl Anal Genom, Barcelona, Spain - Author
‎ IDIBAPS, Unidad Genom, Barcelona, Spain - Author
‎ Pompeu Fabra Univ CRG UPF, Ctr Genom Regulat, Genes & Dis Programme, Barcelona, Spain - Author
‎ Spanish Natl Bioinformat Inst, Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Programme, Madrid, Spain - Author
‎ Univ Barcelona, Programa Conjunto Biol Computac, BSC, IRB,Spanish Natl Bioinformat Inst, Barcelona, Spain - Author
‎ Univ Barcelona, Serv Hematol, Hosp Clin, Barcelona, Spain - Author
‎ Univ Barcelona, Unidad Hematopatol, Serv Anat Patol, Hosp Clin,Inst Invest Biomed August Pi & Sunyer I, Barcelona, Spain - Author
‎ Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, Oviedo, Spain - Author
‎ Univ Salamanca, Serv Hematol, Univ Hosp, Ctr Invest Canc, E-37008 Salamanca, Spain - Author
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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.

Keywords
activationcancer genomeexpressionmyelodysplasiapathwayssomatic mutationsspliceostatinActivationAmino acid sequenceDisease progressionExomeExpressionHumansLeukemia, lymphocytic, chronic, b-cellMutationPathwaysPhosphoproteinsPre-messenger-rnaRibonucleoprotein, u2 small nuclearRna splicing factorsSequence alignmentSf3b1 protein, humanSomatic mutations

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Genetics due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2012, it was in position 2/161, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 15.87. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 17.61 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 68.32 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-25, the following number of citations:

  • WoS: 796
  • Scopus: 863
  • Europe PMC: 601
  • Google Scholar: 1233
  • OpenCitations: 881
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-25:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 772.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 771 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 41.75.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 10 (Altmetric).
Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: New York.