Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation

Takeshi Nagasaka, Hiromi Sasamoto, Kenji Notohara, Harry M. Cullings, Masanori Takeda, Keigo Kimura, Takeshi Kambara, Donald G. MacPhee, Joanne Young, Barbara A. Leggett, Jeremy R. Jass, Noriaki Tanaka, Nagahide Matsubara

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Abstract

Purpose: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1. whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16 INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P <.0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. Conclusion: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

Original languageEnglish
Pages (from-to)4584-4594
Number of pages11
JournalJournal of Clinical Oncology
Volume22
Issue number22
DOIs
Publication statusPublished - 2004
Externally publishedYes

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DNA Methylation
Oncogenes
Colorectal Neoplasms
Mutation
Methylation
DNA Mismatch Repair
Tumor Suppressor Protein p14ARF
DNA Repair-Deficiency Disorders
MAP Kinase Signaling System
Epigenomics
Neoplasms
Carcinogenesis
Mucous Membrane

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. / Nagasaka, Takeshi; Sasamoto, Hiromi; Notohara, Kenji; Cullings, Harry M.; Takeda, Masanori; Kimura, Keigo; Kambara, Takeshi; MacPhee, Donald G.; Young, Joanne; Leggett, Barbara A.; Jass, Jeremy R.; Tanaka, Noriaki; Matsubara, Nagahide.

In: Journal of Clinical Oncology, Vol. 22, No. 22, 2004, p. 4584-4594.

Research output: Contribution to journalArticle

Nagasaka, T, Sasamoto, H, Notohara, K, Cullings, HM, Takeda, M, Kimura, K, Kambara, T, MacPhee, DG, Young, J, Leggett, BA, Jass, JR, Tanaka, N & Matsubara, N 2004, 'Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation', Journal of Clinical Oncology, vol. 22, no. 22, pp. 4584-4594. https://doi.org/10.1200/JCO.2004.02.154
Nagasaka, Takeshi ; Sasamoto, Hiromi ; Notohara, Kenji ; Cullings, Harry M. ; Takeda, Masanori ; Kimura, Keigo ; Kambara, Takeshi ; MacPhee, Donald G. ; Young, Joanne ; Leggett, Barbara A. ; Jass, Jeremy R. ; Tanaka, Noriaki ; Matsubara, Nagahide. / Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 22. pp. 4584-4594.
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abstract = "Purpose: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1. whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16 INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results: BRAF V599E mutations were identified in 21 (9{\%}) of 234 CRCs, and KRAS mutations were identified in 72 (31{\%}) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95{\%} CI, 6.6 to 7.9) among 11 loci examined (P <.0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95{\%} CI, 1.5 to 2.1) and 1.0 (95{\%} CI, 0.79 to 1.3), respectively. Conclusion: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.",
author = "Takeshi Nagasaka and Hiromi Sasamoto and Kenji Notohara and Cullings, {Harry M.} and Masanori Takeda and Keigo Kimura and Takeshi Kambara and MacPhee, {Donald G.} and Joanne Young and Leggett, {Barbara A.} and Jass, {Jeremy R.} and Noriaki Tanaka and Nagahide Matsubara",
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T1 - Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation

AU - Nagasaka, Takeshi

AU - Sasamoto, Hiromi

AU - Notohara, Kenji

AU - Cullings, Harry M.

AU - Takeda, Masanori

AU - Kimura, Keigo

AU - Kambara, Takeshi

AU - MacPhee, Donald G.

AU - Young, Joanne

AU - Leggett, Barbara A.

AU - Jass, Jeremy R.

AU - Tanaka, Noriaki

AU - Matsubara, Nagahide

PY - 2004

Y1 - 2004

N2 - Purpose: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1. whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16 INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P <.0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. Conclusion: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

AB - Purpose: BRAF mutations are common in sporadic colorectal cancers (CRCs) with a DNA mismatch repair (MMR) deficiency that results from promoter methylation of hMLH1. whereas KRAS mutations are common in MMR proficient CRCs associated with promoter methylation of MGMT. The aim of this study was to further investigate the link between genetic alterations in the RAS/RAF/ERK pathway and an underlying epigenetic disorder. Patients and Methods: Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16 INK4a, p14ARF, COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa. Results: BRAF V599E mutations were identified in 21 (9%) of 234 CRCs, and KRAS mutations were identified in 72 (31%) of 234 CRCs. Mutations in BRAF and KRAS were never found in the same tumor. CRCs with BRAF mutations showed high-level promoter methylation in multiple loci, with a mean number of methylated loci of 7.2 (95% CI, 6.6 to 7.9) among 11 loci examined (P <.0001). Tumors with KRAS mutations showed low-level promoter methylation, and CRCs with neither mutation showed a weak association with promoter methylation, with an average number of methylated loci of 1.8 (95% CI, 1.5 to 2.1) and 1.0 (95% CI, 0.79 to 1.3), respectively. Conclusion: In CRC, the methylation status of multiple promoters can be predicted through knowledge of BRAF and, to a lesser extent, KRAS activating mutations, indicating that these mutations are closely associated with different patterns of DNA hypermethylation. These changes may be important events in colorectal tumorigenesis.

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