Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

Fazila Asmar; Vasu Punj; Jesper Aagaard Christensen; Marianne T Pedersen; Anja Pedersen; Anders B Nielsen; Christoffer Hother; Ulrik Ralfkiaer; Peter Brown; Elisabeth Ralfkiaer; Kristian Helin; Kirsten Grønbæk

doi:10.3324/haematol.2013.088740

Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

Fazila Asmar, Vasu Punj, Jesper Aagaard Christensen, Marianne T Pedersen, Anja Pedersen, Anders B Nielsen, Christoffer Hother, Ulrik Ralfkiaer, Peter Brown, Elisabeth Ralfkiaer, Kristian Helin, Kirsten Grønbæk

85 Citations (Scopus)

Abstract

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<0.0001), and at CpG-rich promoters (60%; P<0.0001) of genes involved in hematopoietic differentiation and cellular development. Hypermethylated loci in TET2 mutated samples overlap with the bivalent (H3K27me3/H3K4me3) silencing mark in human embryonic stem cells (P=1.5×10^-30). Surprisingly, gene expression profiling showed that only 11% of the hypermethylated genes were down-regulated, among which there were several genes previously suggested to be tumor suppressors. A metaanalysis suggested that the 35 hypermethylated and down-regulated genes are associated with the activated B-celllike type of diffuse large B-cell lymphoma in other studies. In conclusion, our data suggest that TET2 mutations may cause aberrant methylation mainly of genes involved in hematopoietic development, which are silenced but poised for activation in human embryonic stem cells.

Original language	English
Journal	Haematologica
Volume	98
Issue number	12
Pages (from-to)	1912-20
Number of pages	9
ISSN	0390-6078
DOIs	https://doi.org/10.3324/haematol.2013.088740
Publication status	Published - 1 Dec 2013

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Asmar, F., Punj, V., Christensen, J. A., Pedersen, M. T., Pedersen, A., Nielsen, A. B., Hother, C., Ralfkiaer, U., Brown, P., Ralfkiaer, E., Helin, K., & Grønbæk, K. (2013). Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma. Haematologica, 98(12), 1912-20. https://doi.org/10.3324/haematol.2013.088740

Asmar, F, Punj, V, Christensen, JA , Pedersen, MT, Pedersen, A, Nielsen, AB, Hother, C, Ralfkiaer, U, Brown, P, Ralfkiaer, E, Helin, K & Grønbæk, K 2013, 'Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma', Haematologica, vol. 98, no. 12, pp. 1912-20. https://doi.org/10.3324/haematol.2013.088740

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title = "Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma",

abstract = "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<0.0001), and at CpG-rich promoters (60%; P<0.0001) of genes involved in hematopoietic differentiation and cellular development. Hypermethylated loci in TET2 mutated samples overlap with the bivalent (H3K27me3/H3K4me3) silencing mark in human embryonic stem cells (P=1.5×10-30). Surprisingly, gene expression profiling showed that only 11% of the hypermethylated genes were down-regulated, among which there were several genes previously suggested to be tumor suppressors. A metaanalysis suggested that the 35 hypermethylated and down-regulated genes are associated with the activated B-celllike type of diffuse large B-cell lymphoma in other studies. In conclusion, our data suggest that TET2 mutations may cause aberrant methylation mainly of genes involved in hematopoietic development, which are silenced but poised for activation in human embryonic stem cells.",

author = "Fazila Asmar and Vasu Punj and Christensen, {Jesper Aagaard} and Pedersen, {Marianne T} and Anja Pedersen and Nielsen, {Anders B} and Christoffer Hother and Ulrik Ralfkiaer and Peter Brown and Elisabeth Ralfkiaer and Kristian Helin and Kirsten Gr{\o}nb{\ae}k",

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doi = "10.3324/haematol.2013.088740",

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T1 - Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

AU - Asmar, Fazila

AU - Punj, Vasu

AU - Christensen, Jesper Aagaard

AU - Pedersen, Marianne T

AU - Pedersen, Anja

AU - Nielsen, Anders B

AU - Hother, Christoffer

AU - Ralfkiaer, Ulrik

AU - Brown, Peter

AU - Ralfkiaer, Elisabeth

AU - Helin, Kristian

AU - Grønbæk, Kirsten

PY - 2013/12/1

Y1 - 2013/12/1

N2 - 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<0.0001), and at CpG-rich promoters (60%; P<0.0001) of genes involved in hematopoietic differentiation and cellular development. Hypermethylated loci in TET2 mutated samples overlap with the bivalent (H3K27me3/H3K4me3) silencing mark in human embryonic stem cells (P=1.5×10-30). Surprisingly, gene expression profiling showed that only 11% of the hypermethylated genes were down-regulated, among which there were several genes previously suggested to be tumor suppressors. A metaanalysis suggested that the 35 hypermethylated and down-regulated genes are associated with the activated B-celllike type of diffuse large B-cell lymphoma in other studies. In conclusion, our data suggest that TET2 mutations may cause aberrant methylation mainly of genes involved in hematopoietic development, which are silenced but poised for activation in human embryonic stem cells.

AB - 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<0.0001), and at CpG-rich promoters (60%; P<0.0001) of genes involved in hematopoietic differentiation and cellular development. Hypermethylated loci in TET2 mutated samples overlap with the bivalent (H3K27me3/H3K4me3) silencing mark in human embryonic stem cells (P=1.5×10-30). Surprisingly, gene expression profiling showed that only 11% of the hypermethylated genes were down-regulated, among which there were several genes previously suggested to be tumor suppressors. A metaanalysis suggested that the 35 hypermethylated and down-regulated genes are associated with the activated B-celllike type of diffuse large B-cell lymphoma in other studies. In conclusion, our data suggest that TET2 mutations may cause aberrant methylation mainly of genes involved in hematopoietic development, which are silenced but poised for activation in human embryonic stem cells.

U2 - 10.3324/haematol.2013.088740

DO - 10.3324/haematol.2013.088740

M3 - Journal article

C2 - 23831920

SN - 0390-6078

VL - 98

SP - 1912

EP - 1920

JO - Haematologica

JF - Haematologica

IS - 12

ER -

Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

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