CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

Daniel J. Weisenberger, Kimberly D. Siegmund, Mihaela Campan, Joanne Young, Tiffany I. Long, Mark A. Faasse, Gyeong Hoon Kang, Martin Widschwendter, Deborah Weener, Daniel Buchanan, Hoey Koh, Lisa Simms, Melissa Barker, Barbara Leggett, Joan Levine, Myungjin Kim, Amy J. French, Stephen N Thibodeau, Jeremy Jass, Robert HailePeter W. Laird

Research output: Contribution to journalArticle

1306 Citations (Scopus)

Abstract

Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.

Original languageEnglish (US)
Pages (from-to)787-793
Number of pages7
JournalNature Genetics
Volume38
Issue number7
DOIs
StatePublished - Jul 2006

Fingerprint

Microsatellite Instability
CpG Islands
Colorectal Neoplasms
Methylation
Phenotype
Mutation
Neoplasms
Gene Silencing
DNA Methylation
Odds Ratio
Technology

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Weisenberger, D. J., Siegmund, K. D., Campan, M., Young, J., Long, T. I., Faasse, M. A., ... Laird, P. W. (2006). CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nature Genetics, 38(7), 787-793. https://doi.org/10.1038/ng1834

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. / Weisenberger, Daniel J.; Siegmund, Kimberly D.; Campan, Mihaela; Young, Joanne; Long, Tiffany I.; Faasse, Mark A.; Kang, Gyeong Hoon; Widschwendter, Martin; Weener, Deborah; Buchanan, Daniel; Koh, Hoey; Simms, Lisa; Barker, Melissa; Leggett, Barbara; Levine, Joan; Kim, Myungjin; French, Amy J.; Thibodeau, Stephen N; Jass, Jeremy; Haile, Robert; Laird, Peter W.

In: Nature Genetics, Vol. 38, No. 7, 07.2006, p. 787-793.

Research output: Contribution to journalArticle

Weisenberger, DJ, Siegmund, KD, Campan, M, Young, J, Long, TI, Faasse, MA, Kang, GH, Widschwendter, M, Weener, D, Buchanan, D, Koh, H, Simms, L, Barker, M, Leggett, B, Levine, J, Kim, M, French, AJ, Thibodeau, SN, Jass, J, Haile, R & Laird, PW 2006, 'CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer', Nature Genetics, vol. 38, no. 7, pp. 787-793. https://doi.org/10.1038/ng1834
Weisenberger, Daniel J. ; Siegmund, Kimberly D. ; Campan, Mihaela ; Young, Joanne ; Long, Tiffany I. ; Faasse, Mark A. ; Kang, Gyeong Hoon ; Widschwendter, Martin ; Weener, Deborah ; Buchanan, Daniel ; Koh, Hoey ; Simms, Lisa ; Barker, Melissa ; Leggett, Barbara ; Levine, Joan ; Kim, Myungjin ; French, Amy J. ; Thibodeau, Stephen N ; Jass, Jeremy ; Haile, Robert ; Laird, Peter W. / CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. In: Nature Genetics. 2006 ; Vol. 38, No. 7. pp. 787-793.
@article{2cb4f5da59b74791b5ccc404e76d00dc,
title = "CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer",
abstract = "Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.",
author = "Weisenberger, {Daniel J.} and Siegmund, {Kimberly D.} and Mihaela Campan and Joanne Young and Long, {Tiffany I.} and Faasse, {Mark A.} and Kang, {Gyeong Hoon} and Martin Widschwendter and Deborah Weener and Daniel Buchanan and Hoey Koh and Lisa Simms and Melissa Barker and Barbara Leggett and Joan Levine and Myungjin Kim and French, {Amy J.} and Thibodeau, {Stephen N} and Jeremy Jass and Robert Haile and Laird, {Peter W.}",
year = "2006",
month = "7",
doi = "10.1038/ng1834",
language = "English (US)",
volume = "38",
pages = "787--793",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

AU - Weisenberger, Daniel J.

AU - Siegmund, Kimberly D.

AU - Campan, Mihaela

AU - Young, Joanne

AU - Long, Tiffany I.

AU - Faasse, Mark A.

AU - Kang, Gyeong Hoon

AU - Widschwendter, Martin

AU - Weener, Deborah

AU - Buchanan, Daniel

AU - Koh, Hoey

AU - Simms, Lisa

AU - Barker, Melissa

AU - Leggett, Barbara

AU - Levine, Joan

AU - Kim, Myungjin

AU - French, Amy J.

AU - Thibodeau, Stephen N

AU - Jass, Jeremy

AU - Haile, Robert

AU - Laird, Peter W.

PY - 2006/7

Y1 - 2006/7

N2 - Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.

AB - Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1. We propose a robust new marker panel to classify CIMP+ tumors.

UR - http://www.scopus.com/inward/record.url?scp=33745541234&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745541234&partnerID=8YFLogxK

U2 - 10.1038/ng1834

DO - 10.1038/ng1834

M3 - Article

C2 - 16804544

AN - SCOPUS:33745541234

VL - 38

SP - 787

EP - 793

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 7

ER -