Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas

P Wang; Q Dong; Chun Zhang; P-F Kuan; Y Liu; W R Jeck; Jesper Bøje Andersen; W Jiang; G L Savich; T-X Tan; J T Auman; J M Hoskins; A D Misher; C D Moser; S M Yourstone; J W Kim; K Cibulskis; G Getz; H V Hunt; S S Thorgeirsson; L R Roberts; D Ye; K-L Guan; Y Xiong; L-X Qin; D Y Chiang

doi:10.1038/onc.2012.315

Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas

P Wang, Q Dong, Chun Zhang, P-F Kuan, Y Liu, W R Jeck, Jesper Bøje Andersen, W Jiang, G L Savich, T-X Tan, J T Auman, J M Hoskins, A D Misher, C D Moser, S M Yourstone, J W Kim, K Cibulskis, G Getz, H V Hunt, S S ThorgeirssonL R Roberts, D Ye, K-L Guan, Y Xiong, L-X Qin, D Y Chiang

228 Citations (Scopus)

Abstract

Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

Original language	English
Journal	Oncogene
Volume	32
Issue number	25
Pages (from-to)	3091-100
Number of pages	10
ISSN	0950-9232
DOIs	https://doi.org/10.1038/onc.2012.315
Publication status	Published - 20 Jun 2013
Externally published	Yes

Keywords

Base Sequence
Bile Duct Neoplasms
Bile Ducts, Intrahepatic
Brain Neoplasms
Cholangiocarcinoma
CpG Islands
DNA Methylation
Glioblastoma
Histones
Humans
Isocitrate Dehydrogenase
Liver Neoplasms
Mutation
Neoplasm Recurrence, Local
Sequence Analysis, DNA
Tumor Suppressor Protein p53

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/onc.2012.315

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Wang, P., Dong, Q., Zhang, C., Kuan, P-F., Liu, Y., Jeck, W. R., Andersen, J. B., Jiang, W., Savich, G. L., Tan, T-X., Auman, J. T., Hoskins, J. M., Misher, A. D., Moser, C. D., Yourstone, S. M., Kim, J. W., Cibulskis, K., Getz, G., Hunt, H. V., ... Chiang, D. Y. (2013). Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene, 32(25), 3091-100. https://doi.org/10.1038/onc.2012.315

Wang, P, Dong, Q, Zhang, C, Kuan, P-F, Liu, Y, Jeck, WR, Andersen, JB, Jiang, W, Savich, GL, Tan, T-X, Auman, JT, Hoskins, JM, Misher, AD, Moser, CD, Yourstone, SM, Kim, JW, Cibulskis, K, Getz, G, Hunt, HV, Thorgeirsson, SS, Roberts, LR, Ye, D, Guan, K-L, Xiong, Y, Qin, L-X & Chiang, DY 2013, 'Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas', Oncogene, vol. 32, no. 25, pp. 3091-100. https://doi.org/10.1038/onc.2012.315

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title = "Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas",

abstract = "Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.",

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T1 - Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas

AU - Wang, P

AU - Dong, Q

AU - Zhang, Chun

AU - Kuan, P-F

AU - Liu, Y

AU - Jeck, W R

AU - Andersen, Jesper Bøje

AU - Jiang, W

AU - Savich, G L

AU - Tan, T-X

AU - Auman, J T

AU - Hoskins, J M

AU - Misher, A D

AU - Moser, C D

AU - Yourstone, S M

AU - Kim, J W

AU - Cibulskis, K

AU - Getz, G

AU - Hunt, H V

AU - Thorgeirsson, S S

AU - Roberts, L R

AU - Ye, D

AU - Guan, K-L

AU - Xiong, Y

AU - Qin, L-X

AU - Chiang, D Y

PY - 2013/6/20

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N2 - Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

AB - Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

KW - Base Sequence

KW - Bile Duct Neoplasms

KW - Bile Ducts, Intrahepatic

KW - Brain Neoplasms

KW - Cholangiocarcinoma

KW - CpG Islands

KW - DNA Methylation

KW - Glioblastoma

KW - Histones

KW - Humans

KW - Isocitrate Dehydrogenase

KW - Liver Neoplasms

KW - Mutation

KW - Neoplasm Recurrence, Local

KW - Sequence Analysis, DNA

KW - Tumor Suppressor Protein p53

U2 - 10.1038/onc.2012.315

DO - 10.1038/onc.2012.315

M3 - Journal article

C2 - 22824796

SN - 0950-9232

VL - 32

SP - 3091

EP - 3100

JO - Oncogene

JF - Oncogene

IS - 25

ER -

Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas

Abstract

Keywords

UN SDGs

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