Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas

Eri Arai, Suenori Chiku, Taisuke Mori, Masahiro Gotoh, Tohru Nakagawa, Hiroyuki Fujimoto, Yae Kanai

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Abstract

To clarify the significance of DNA methylation alterations during renal carcinogenesis, methylome analysis using single-CpG-resolution Infinium array was performed on 29 normal renal cortex tissue (C) samples, 107 non-cancerous renal cortex tissue (N) samples obtained from patients with clear cell renal cell carcinomas (RCCs) and 109 tumorous tissue (T) samples. DNA methylation levels at 4830 CpG sites were already altered in N samples compared with C samples. Unsupervised hierarchical clustering analysis based on DNA methylation levels at the 801 CpG sites, where DNA methylation alterations had occurred in N samples and were inherited by and strengthened in T samples, clustered clear cell RCCs into Cluster A (n = 90) and Cluster B (n = 14). Clinicopathologically aggressive tumors were accumulated in Cluster B, and the cancer-free and overall survival rates of patients in this cluster were significantly lower than those of patients in Cluster A. Clear cell RCCs in Cluster B were characterized by accumulation of DNA hypermethylation on CpG islands and considered to be CpG island methylator phenotype (CIMP)-positive cancers. DNA hypermethylation of the CpG sites on the FAM150A, GRM6, ZNF540, ZFP42, ZNF154, RIMS4, PCDHAC1, KHDRBS2, ASCL2, KCNQ1, PRAC, WNT3A, TRH, FAM78A, ZNF671, SLC13A5 and NKX6-2 genes became hallmarks of CIMP in RCCs. On the other hand, Cluster A was characterized by genome-wide DNA hypomethylation. These data indicated that DNA methylation alterations at precancerous stages may determine tumor aggressiveness and patient outcome. Accumulation of DNA hypermethylation on CpG islands and genome-wide DNA hypomethylation may each underlie distinct pathways of renal carcinogenesis. Abbreviations: BAMCAbacterial artificial chromosome array-based methylated CpG island amplification. Cnormal renal cortex tissue obtained from patients without any primary renal tumor. CIMPCpG island methylator phenotype. HCChepatocellular carcinoma. Nnon-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas. NCBINational Center for Biotechnology Information. RCCrenal cell carcinoma. Ttumorous tissue. TNMTumor-Node-Metastasis.

Original languageEnglish
Pages (from-to)1487-1493
Number of pages7
JournalCarcinogenesis
Volume33
Issue number8
DOIs
Publication statusPublished - 2012 Aug
Externally publishedYes

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CpG Islands
Renal Cell Carcinoma
DNA Methylation
Phenotype
Kidney
DNA
Neoplasms
Carcinogenesis
Artificial Chromosomes
Genome
Carcinoma
Information Centers
Biotechnology
Islands
Cluster Analysis
Survival Rate
Neoplasm Metastasis
Genes

ASJC Scopus subject areas

  • Cancer Research

Cite this

Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. / Arai, Eri; Chiku, Suenori; Mori, Taisuke; Gotoh, Masahiro; Nakagawa, Tohru; Fujimoto, Hiroyuki; Kanai, Yae.

In: Carcinogenesis, Vol. 33, No. 8, 08.2012, p. 1487-1493.

Research output: Contribution to journalArticle

Arai, Eri ; Chiku, Suenori ; Mori, Taisuke ; Gotoh, Masahiro ; Nakagawa, Tohru ; Fujimoto, Hiroyuki ; Kanai, Yae. / Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. In: Carcinogenesis. 2012 ; Vol. 33, No. 8. pp. 1487-1493.
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AU - Arai, Eri

AU - Chiku, Suenori

AU - Mori, Taisuke

AU - Gotoh, Masahiro

AU - Nakagawa, Tohru

AU - Fujimoto, Hiroyuki

AU - Kanai, Yae

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N2 - To clarify the significance of DNA methylation alterations during renal carcinogenesis, methylome analysis using single-CpG-resolution Infinium array was performed on 29 normal renal cortex tissue (C) samples, 107 non-cancerous renal cortex tissue (N) samples obtained from patients with clear cell renal cell carcinomas (RCCs) and 109 tumorous tissue (T) samples. DNA methylation levels at 4830 CpG sites were already altered in N samples compared with C samples. Unsupervised hierarchical clustering analysis based on DNA methylation levels at the 801 CpG sites, where DNA methylation alterations had occurred in N samples and were inherited by and strengthened in T samples, clustered clear cell RCCs into Cluster A (n = 90) and Cluster B (n = 14). Clinicopathologically aggressive tumors were accumulated in Cluster B, and the cancer-free and overall survival rates of patients in this cluster were significantly lower than those of patients in Cluster A. Clear cell RCCs in Cluster B were characterized by accumulation of DNA hypermethylation on CpG islands and considered to be CpG island methylator phenotype (CIMP)-positive cancers. DNA hypermethylation of the CpG sites on the FAM150A, GRM6, ZNF540, ZFP42, ZNF154, RIMS4, PCDHAC1, KHDRBS2, ASCL2, KCNQ1, PRAC, WNT3A, TRH, FAM78A, ZNF671, SLC13A5 and NKX6-2 genes became hallmarks of CIMP in RCCs. On the other hand, Cluster A was characterized by genome-wide DNA hypomethylation. These data indicated that DNA methylation alterations at precancerous stages may determine tumor aggressiveness and patient outcome. Accumulation of DNA hypermethylation on CpG islands and genome-wide DNA hypomethylation may each underlie distinct pathways of renal carcinogenesis. Abbreviations: BAMCAbacterial artificial chromosome array-based methylated CpG island amplification. Cnormal renal cortex tissue obtained from patients without any primary renal tumor. CIMPCpG island methylator phenotype. HCChepatocellular carcinoma. Nnon-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas. NCBINational Center for Biotechnology Information. RCCrenal cell carcinoma. Ttumorous tissue. TNMTumor-Node-Metastasis.

AB - To clarify the significance of DNA methylation alterations during renal carcinogenesis, methylome analysis using single-CpG-resolution Infinium array was performed on 29 normal renal cortex tissue (C) samples, 107 non-cancerous renal cortex tissue (N) samples obtained from patients with clear cell renal cell carcinomas (RCCs) and 109 tumorous tissue (T) samples. DNA methylation levels at 4830 CpG sites were already altered in N samples compared with C samples. Unsupervised hierarchical clustering analysis based on DNA methylation levels at the 801 CpG sites, where DNA methylation alterations had occurred in N samples and were inherited by and strengthened in T samples, clustered clear cell RCCs into Cluster A (n = 90) and Cluster B (n = 14). Clinicopathologically aggressive tumors were accumulated in Cluster B, and the cancer-free and overall survival rates of patients in this cluster were significantly lower than those of patients in Cluster A. Clear cell RCCs in Cluster B were characterized by accumulation of DNA hypermethylation on CpG islands and considered to be CpG island methylator phenotype (CIMP)-positive cancers. DNA hypermethylation of the CpG sites on the FAM150A, GRM6, ZNF540, ZFP42, ZNF154, RIMS4, PCDHAC1, KHDRBS2, ASCL2, KCNQ1, PRAC, WNT3A, TRH, FAM78A, ZNF671, SLC13A5 and NKX6-2 genes became hallmarks of CIMP in RCCs. On the other hand, Cluster A was characterized by genome-wide DNA hypomethylation. These data indicated that DNA methylation alterations at precancerous stages may determine tumor aggressiveness and patient outcome. Accumulation of DNA hypermethylation on CpG islands and genome-wide DNA hypomethylation may each underlie distinct pathways of renal carcinogenesis. Abbreviations: BAMCAbacterial artificial chromosome array-based methylated CpG island amplification. Cnormal renal cortex tissue obtained from patients without any primary renal tumor. CIMPCpG island methylator phenotype. HCChepatocellular carcinoma. Nnon-cancerous renal cortex tissue obtained from patients with clear cell renal cell carcinomas. NCBINational Center for Biotechnology Information. RCCrenal cell carcinoma. Ttumorous tissue. TNMTumor-Node-Metastasis.

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