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Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas

Publication ,  Conference
Wang, P; Dong, Q-Z; Zhang, C; Kuan, P-F; Liu, Y; Jeck, WR; Andersen, JB; Auman, JT; Hoskins, JM; Kim, JW; Cibulskis, K; Getz, G; Hunt, HV ...
Published in: Cancer Research
April 15, 2012

Cholangiocarcinomas are rare but aggressive cancers, with an increasing incidence and a dismal 5-year survival rate of less than 5%. Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in ∼70% of gliomas, ∼20% of myeloid leukemias, ∼56% of chondrosarcomas, and ∼10% of melanomas. We discovered IDH1 and IDH2 mutations in 29 of 305 (9%) intrahepatic cholangiocarcinomas. Tumors with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3K79. Mutations in IDH1 or IDH2 were independently associated with longer time to recurrence of cholangiocarcinoma in multivariate analysis (p = 0.046). We identified 2,267 genes that were significantly hypermethylated in tumors with mutations in IDH1 or IDH2. Hypermethylated CpG sites were significantly enriched in CpG shores and in the 1500 bp upstream of annotated transcription start sites, suggesting a global regulation of transcriptional potential. Gene expression profiling of 7 IDH1/2-mutant and 20 IDH1/2-wildtype tumors revealed increased expression of citric acid cycle and oxidative phosphorylation enzymes, as well as decreased expression of cytoskeleton organization genes. Integrated analyses of DNA methylation and gene expression identified interleukin-6 and several of its downstream targets as candidates for silencing by DNA methylation. Conclusions: Cholangiocarcinomas with mutations in IDH1 or IDH2 represent a molecular subclass with distinct signaling pathway alterations.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1058. doi:1538-7445.AM2012-1058

Duke Scholars

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

April 15, 2012

Volume

72

Issue

8_Supplement

Start / End Page

1058 / 1058

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, P., Dong, Q.-Z., Zhang, C., Kuan, P.-F., Liu, Y., Jeck, W. R., … Chiang, D. Y. (2012). Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas. In Cancer Research (Vol. 72, pp. 1058–1058). American Association for Cancer Research (AACR). https://doi.org/10.1158/1538-7445.am2012-1058
Wang, Pu, Qiong-Zhu Dong, Chong Zhang, Pei-Fen Kuan, Yufeng Liu, William R. Jeck, Jesper B. Andersen, et al. “Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas.” In Cancer Research, 72:1058–1058. American Association for Cancer Research (AACR), 2012. https://doi.org/10.1158/1538-7445.am2012-1058.
Wang P, Dong Q-Z, Zhang C, Kuan P-F, Liu Y, Jeck WR, et al. Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas. In: Cancer Research. American Association for Cancer Research (AACR); 2012. p. 1058–1058.
Wang, Pu, et al. “Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas.” Cancer Research, vol. 72, no. 8_Supplement, American Association for Cancer Research (AACR), 2012, pp. 1058–1058. Crossref, doi:10.1158/1538-7445.am2012-1058.
Wang P, Dong Q-Z, Zhang C, Kuan P-F, Liu Y, Jeck WR, Andersen JB, Auman JT, Hoskins JM, Kim JW, Cibulskis K, Getz G, Hunt HV, Thorgeirsson SS, Roberts LR, Ye D, Guan K-L, Xiong Y, Qin L-X, Chiang DY. Abstract 1058: Mutations in isocitrate dehydrogenase 1 and 2 are associated with DNA hypermethylation in intrahepatic cholangiocarcinomas. Cancer Research. American Association for Cancer Research (AACR); 2012. p. 1058–1058.

Published In

Cancer Research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

April 15, 2012

Volume

72

Issue

8_Supplement

Start / End Page

1058 / 1058

Publisher

American Association for Cancer Research (AACR)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis