DNA methylation predicts recurrence from resected stage III proximal colon cancer

Joong Bae Ahn, Woon Bok Chung, Osamu Maeda, Sang Joon Shin, Hyunsoo Kim, Hyuncheol Chung, Namkyu Kim, Jean Pierre J. Issa

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

BACKGROUND: In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated. METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed. RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P =.015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P =.049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P =.008 for classification by K-means clustering analysis; P =.040 for LINE-1 methylation status). CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings. Cancer 2011;117:1847-1854.

Original languageEnglish
Pages (from-to)1847-1854
Number of pages8
JournalCancer
Volume117
Issue number9
DOIs
Publication statusPublished - 2011 May 1

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DNA Methylation
CpG Islands
Colonic Neoplasms
Colorectal Neoplasms
Recurrence
Phenotype
Methylation
Disease-Free Survival
Mutation
Cluster Analysis
Neoplasms
Genetic Markers
Multivariate Analysis
Biomarkers
Genes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ahn, J. B., Chung, W. B., Maeda, O., Shin, S. J., Kim, H., Chung, H., ... Issa, J. P. J. (2011). DNA methylation predicts recurrence from resected stage III proximal colon cancer. Cancer, 117(9), 1847-1854. https://doi.org/10.1002/cncr.25737
Ahn, Joong Bae ; Chung, Woon Bok ; Maeda, Osamu ; Shin, Sang Joon ; Kim, Hyunsoo ; Chung, Hyuncheol ; Kim, Namkyu ; Issa, Jean Pierre J. / DNA methylation predicts recurrence from resected stage III proximal colon cancer. In: Cancer. 2011 ; Vol. 117, No. 9. pp. 1847-1854.
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title = "DNA methylation predicts recurrence from resected stage III proximal colon cancer",
abstract = "BACKGROUND: In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated. METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed. RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7{\%}), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8{\%}), associated with KRAS mutations; and CIMP-negative (n = 99, 61.5{\%}), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53{\%} for CIMP1, 18{\%} for CIMP2, and 26{\%} for CIMP-negative) and a worse DFS (P =.015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P =.049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P =.008 for classification by K-means clustering analysis; P =.040 for LINE-1 methylation status). CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings. Cancer 2011;117:1847-1854.",
author = "Ahn, {Joong Bae} and Chung, {Woon Bok} and Osamu Maeda and Shin, {Sang Joon} and Hyunsoo Kim and Hyuncheol Chung and Namkyu Kim and Issa, {Jean Pierre J.}",
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DNA methylation predicts recurrence from resected stage III proximal colon cancer. / Ahn, Joong Bae; Chung, Woon Bok; Maeda, Osamu; Shin, Sang Joon; Kim, Hyunsoo; Chung, Hyuncheol; Kim, Namkyu; Issa, Jean Pierre J.

In: Cancer, Vol. 117, No. 9, 01.05.2011, p. 1847-1854.

Research output: Contribution to journalArticle

TY - JOUR

T1 - DNA methylation predicts recurrence from resected stage III proximal colon cancer

AU - Ahn, Joong Bae

AU - Chung, Woon Bok

AU - Maeda, Osamu

AU - Shin, Sang Joon

AU - Kim, Hyunsoo

AU - Chung, Hyuncheol

AU - Kim, Namkyu

AU - Issa, Jean Pierre J.

PY - 2011/5/1

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N2 - BACKGROUND: In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated. METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed. RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P =.015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P =.049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P =.008 for classification by K-means clustering analysis; P =.040 for LINE-1 methylation status). CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings. Cancer 2011;117:1847-1854.

AB - BACKGROUND: In colorectal cancer (CRC), DNA methylation anomalies define distinct subgroups termed CpG island methylator phenotype 1 (CIMP1), CIMP2, and CIMP-negative. The role of this classification in predicting recurrence and disease-free survival (DFS) in resected stage III CRC was evaluated. METHODS: Sporadic cancers from 161 patients were analyzed. Bisulfite pyrosequencing was used to examine the methylation of 2 global DNA methylation markers (LINE-1, Alu) and 9 loci (MINT1, MINT2, MINT31, P16, hMLH1, P14, SFRP1, SFRP2, and WNT5A). Mutations in BRAF and KRAS were assayed. RESULTS: Gene hypermethylation clustered in discrete groups of patients, indicating the presence of CIMP. K-means clustering analysis identified 3 discrete subgroups: CIMP1 (n = 22, 13.7%), associated with proximal location and BRAF mutations; CIMP2 (n = 40, 24.8%), associated with KRAS mutations; and CIMP-negative (n = 99, 61.5%), associated with distal location. In proximal CRC, CIMP1 was correlated with a higher recurrence rate (53% for CIMP1, 18% for CIMP2, and 26% for CIMP-negative) and a worse DFS (P =.015). Also in proximal CRC, LINE-1 methylation was lower in patients whose cancer recurred compared with those whose cancer did not recur (P =.049). In multivariate analysis, CIMP1 and low LINE1 methylation were independent prognostic factors for DFS in proximal CRC (P =.008 for classification by K-means clustering analysis; P =.040 for LINE-1 methylation status). CONCLUSIONS: DNA methylation is a useful biomarker of recurrence in resected stage III proximal but not distal CRC. However, as the number of CIMP1 cases was small in distal CRC, further study is required to validate our findings. Cancer 2011;117:1847-1854.

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