Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival

Caroline Y. Hu, Davoud Mohtat, Yiting Yu, Yi An Ko, Niraj Shenoy, Sanchari Bhattacharya, Maria C. Izquierdo, Ae Seo Deok Park, Orsolya Giricz, Nishanth Vallumsetla, Krishna Gundabolu, Kristin Ware, Tushar D. Bhagat, Masako Suzuki, James Pullman, X. Shirley Liu, John M. Greally, Katalin Susztak, Amit Verma

Research output: Contribution to journalArticle

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Abstract

Purpose: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. Experimental Design: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls. Results: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases ofRCCin multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients. Conclusions: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.

Original languageEnglish (US)
Pages (from-to)4349-4360
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number16
DOIs
StatePublished - Aug 15 2014

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Choristoma
Kidney Neoplasms
Renal Cell Carcinoma
Methylation
Survival
decitabine
Kidney
Epigenomics
Cytosine
DNA Methylation
Genes
Carcinogenesis
Research Design
Transcription Factors
Multivariate Analysis
Binding Sites
Genome
Mutation
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival. / Hu, Caroline Y.; Mohtat, Davoud; Yu, Yiting; Ko, Yi An; Shenoy, Niraj; Bhattacharya, Sanchari; Izquierdo, Maria C.; Park, Ae Seo Deok; Giricz, Orsolya; Vallumsetla, Nishanth; Gundabolu, Krishna; Ware, Kristin; Bhagat, Tushar D.; Suzuki, Masako; Pullman, James; Liu, X. Shirley; Greally, John M.; Susztak, Katalin; Verma, Amit.

In: Clinical Cancer Research, Vol. 20, No. 16, 15.08.2014, p. 4349-4360.

Research output: Contribution to journalArticle

Hu, CY, Mohtat, D, Yu, Y, Ko, YA, Shenoy, N, Bhattacharya, S, Izquierdo, MC, Park, ASD, Giricz, O, Vallumsetla, N, Gundabolu, K, Ware, K, Bhagat, TD, Suzuki, M, Pullman, J, Liu, XS, Greally, JM, Susztak, K & Verma, A 2014, 'Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival', Clinical Cancer Research, vol. 20, no. 16, pp. 4349-4360. https://doi.org/10.1158/1078-0432.CCR-14-0494
Hu, Caroline Y. ; Mohtat, Davoud ; Yu, Yiting ; Ko, Yi An ; Shenoy, Niraj ; Bhattacharya, Sanchari ; Izquierdo, Maria C. ; Park, Ae Seo Deok ; Giricz, Orsolya ; Vallumsetla, Nishanth ; Gundabolu, Krishna ; Ware, Kristin ; Bhagat, Tushar D. ; Suzuki, Masako ; Pullman, James ; Liu, X. Shirley ; Greally, John M. ; Susztak, Katalin ; Verma, Amit. / Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 16. pp. 4349-4360.
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abstract = "Purpose: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. Experimental Design: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls. Results: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases ofRCCin multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients. Conclusions: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.",
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T1 - Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival

AU - Hu, Caroline Y.

AU - Mohtat, Davoud

AU - Yu, Yiting

AU - Ko, Yi An

AU - Shenoy, Niraj

AU - Bhattacharya, Sanchari

AU - Izquierdo, Maria C.

AU - Park, Ae Seo Deok

AU - Giricz, Orsolya

AU - Vallumsetla, Nishanth

AU - Gundabolu, Krishna

AU - Ware, Kristin

AU - Bhagat, Tushar D.

AU - Suzuki, Masako

AU - Pullman, James

AU - Liu, X. Shirley

AU - Greally, John M.

AU - Susztak, Katalin

AU - Verma, Amit

PY - 2014/8/15

Y1 - 2014/8/15

N2 - Purpose: Even though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. Experimental Design: Analysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls. Results: We observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases ofRCCin multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients. Conclusions: Our study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.

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