Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma
Fazila Asmar,
Vasu Punj,
Jesper Christensen,
Marianne T. Pedersen,
Anja Pedersen,
Anders B. Nielsen,
Christoffer Hother,
Ulrik Ralfkiaer,
Peter Brown,
Elisabeth Ralfkiaer,
Kristian Helin,
Kirsten Grønbæk
Affiliations
Fazila Asmar
Department of Hematology, Rigshospitalet, Copenhagen, Denmark;DanStem, University of Copenhagen, Copenhagen, Denmark
Vasu Punj
Norris Comprehensive Cancer Center Bioinformatics Core and Division of Hematology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Jesper Christensen
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Marianne T. Pedersen
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
Anja Pedersen
Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Anders B. Nielsen
Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Christoffer Hother
Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Ulrik Ralfkiaer
Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Peter Brown
Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Elisabeth Ralfkiaer
Department of Pathology, Rigshospitalet, Copenhagen, Denmark
Kristian Helin
Centre for Epigenetics, University of Copenhagen, Copenhagen, Denmark;Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark;DanStem, University of Copenhagen, Copenhagen, Denmark
Kirsten Grønbæk
Department of Hematology, Rigshospitalet, Copenhagen, Denmark;DanStem, University of Copenhagen, Copenhagen, Denmark
The discovery that the Ten-Eleven Translocation (TET) hydroxylases cause DNA demethylation has fundamentally changed the notion of how DNA methylation is regulated. Clonal analysis of the hematopoetic stem cell compartment suggests that TET2 mutations can be early events in hematologic cancers and recent investigations have shown TET2 mutations in diffuse large B-cell lymphoma. However, the detection rates and the types of TET2 mutations vary, and the relation to global methylation patterns has not been investigated. Here, we show TET2 mutations in 12 of 100 diffuse large B-cell lymphomas with 7% carrying loss-of-function and 5% carrying missense mutations. Genome-wide methylation profiling using 450K Illumina arrays identified 315 differentially methylated genes between TET2 mutated and TET2 wild-type cases. TET2 mutations are primarily associated with hypermethylation within CpG islands (70%; P
