Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer

Takeshi Nagasaka, Minoru Koi, Matthias Kloor, Johannes Gebert, Alex Vilkin, Naoshi Nishida, Sung Kwan Shin, Hiromi Sasamoto, Noriaki Tanaka, Nagahide Matsubara, C. Richard Boland, Ajay Goel

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Background & Aims: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. Methods: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. Results: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P <.0001) or BRAF/KRAS wild-type tumors (0.7, P <.0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). Conclusions: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.

Original languageEnglish
JournalGastroenterology
Volume134
Issue number7
DOIs
Publication statusPublished - Jun 2008
Externally publishedYes

Fingerprint

CpG Islands
Colonic Neoplasms
Colorectal Neoplasms
Phenotype
Mutation
Hereditary Nonpolyposis Colorectal Neoplasms
Methylation
Microsatellite Instability
Neoplasms
DNA Methylation
Epigenomics

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Nagasaka, T., Koi, M., Kloor, M., Gebert, J., Vilkin, A., Nishida, N., ... Goel, A. (2008). Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer. Gastroenterology, 134(7). https://doi.org/10.1053/j.gastro.2008.02.094

Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer. / Nagasaka, Takeshi; Koi, Minoru; Kloor, Matthias; Gebert, Johannes; Vilkin, Alex; Nishida, Naoshi; Shin, Sung Kwan; Sasamoto, Hiromi; Tanaka, Noriaki; Matsubara, Nagahide; Boland, C. Richard; Goel, Ajay.

In: Gastroenterology, Vol. 134, No. 7, 06.2008.

Research output: Contribution to journalArticle

Nagasaka, T, Koi, M, Kloor, M, Gebert, J, Vilkin, A, Nishida, N, Shin, SK, Sasamoto, H, Tanaka, N, Matsubara, N, Boland, CR & Goel, A 2008, 'Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer', Gastroenterology, vol. 134, no. 7. https://doi.org/10.1053/j.gastro.2008.02.094
Nagasaka, Takeshi ; Koi, Minoru ; Kloor, Matthias ; Gebert, Johannes ; Vilkin, Alex ; Nishida, Naoshi ; Shin, Sung Kwan ; Sasamoto, Hiromi ; Tanaka, Noriaki ; Matsubara, Nagahide ; Boland, C. Richard ; Goel, Ajay. / Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer. In: Gastroenterology. 2008 ; Vol. 134, No. 7.
@article{32748d386e574e8a80ce729081b8e402,
title = "Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer",
abstract = "Background & Aims: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. Methods: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. Results: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P <.0001) or BRAF/KRAS wild-type tumors (0.7, P <.0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). Conclusions: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.",
author = "Takeshi Nagasaka and Minoru Koi and Matthias Kloor and Johannes Gebert and Alex Vilkin and Naoshi Nishida and Shin, {Sung Kwan} and Hiromi Sasamoto and Noriaki Tanaka and Nagahide Matsubara and Boland, {C. Richard} and Ajay Goel",
year = "2008",
month = "6",
doi = "10.1053/j.gastro.2008.02.094",
language = "English",
volume = "134",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "7",

}

TY - JOUR

T1 - Mutations in Both KRAS and BRAF May Contribute to the Methylator Phenotype in Colon Cancer

AU - Nagasaka, Takeshi

AU - Koi, Minoru

AU - Kloor, Matthias

AU - Gebert, Johannes

AU - Vilkin, Alex

AU - Nishida, Naoshi

AU - Shin, Sung Kwan

AU - Sasamoto, Hiromi

AU - Tanaka, Noriaki

AU - Matsubara, Nagahide

AU - Boland, C. Richard

AU - Goel, Ajay

PY - 2008/6

Y1 - 2008/6

N2 - Background & Aims: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. Methods: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. Results: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P <.0001) or BRAF/KRAS wild-type tumors (0.7, P <.0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). Conclusions: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.

AB - Background & Aims: Colorectal cancers (CRCs) with the CpG island methylator phenotype (CIMP) often associate with epigenetic silencing of hMLH1 and an activating mutation in the BRAF gene. However, the current CIMP criteria are ambiguous and often result in an underestimation of CIMP frequencies in CRCs. Because BRAF and KRAS belong to same signaling pathway, we hypothesized that not only mutations in BRAF but mutant KRAS may also associate with CIMP in CRC. Methods: We determined the methylation status in a panel of 14 markers (7 canonical CIMP-related loci and 7 new loci), microsatellite instability status, and BRAF/KRAS mutations in a collection of 487 colorectal tissues that included both sporadic and Lynch syndrome patients. Results: Methylation analysis of 7 CIMP-related markers revealed that the mean number of methylated loci was highest in BRAF-mutated CRCs (3.6) vs KRAS-mutated (1.2, P <.0001) or BRAF/KRAS wild-type tumors (0.7, P <.0001). However, analyses with 7 additional markers showed that the mean number of methylated loci in BRAF mutant tumors (4.4) was the same as in KRAS mutant CRCs (4.3, P = .8610). Although sporadic microsatellite instability high tumors had the highest average number of methylated markers (8.4), surprisingly, Lynch syndrome CRCs also demonstrated frequent methylation (5.1). Conclusions: CIMP in CRC may result from activating mutations in either BRAF or KRAS, and the inclusion of additional methylation markers that correlate with mutant KRAS may help clarify CIMP in future studies. Additionally, aberrant DNA methylation is a common event not only in sporadic CRC but also in Lynch syndrome CRCs.

UR - http://www.scopus.com/inward/record.url?scp=44849132638&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44849132638&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2008.02.094

DO - 10.1053/j.gastro.2008.02.094

M3 - Article

C2 - 18435933

AN - SCOPUS:44849132638

VL - 134

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 7

ER -