Highly methylated genes in colorectal neoplasia: Implications for screening

Hongzhi Zou, Jonathan J. Harrington, Abdirashid M. Shire, Rafaela L. Rego, Liang Wang, Megan E. Campbell, Ann L Oberg, David A. Ahlquist

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Discriminant markers are required for accurate cancer screening. We evaluated genes frequently methylated in colorectal neoplasia to identify the most discriminant ones. Four genes specifically methylated in colorectal cancer [bone morphogenetic protein 3 (BMP3), EYA2, aristaless-like homeobox-4 (ALX4), and vimentin] were selected from 41 candidate genes and evaluated on 74 cancers, 62 adenomas, and 70 normal epithelia. Methylation status was analyzed qualitatively and quantitatively and confirmed by bisulfite genomic sequencing. Effect of methylation on gene expression was evaluated in five colon cancer cell lines. K-ras and BRAF mutations were detected by sequencing. Methylation of BMP3, EYA2, ALX4, or vimentin was detected respectively in 66%, 66%, 68%, and 72% of cancers; 74%, 48%, 89%, and 84% of adenomas; and 7%, 5%, 11%, and 11% of normal epithelia (P < 0.01, cancer or adenoma versus normal). Based on area under the curve analyses, discrimination was not significantly improved by combining markers. Comethylation was frequent (two genes or more in 72% of cancers and 84% of adenomas), associated with proximal neoplasm site (P < 0.001), and linked with both BRAF and K-ras mutations (P < 0.01). Cell line experiments supported silencing of expression by methylation in all four study genes. This study shows BMP3, EYA2, ALX4, and vimentin genes are methylated in most colorectal neoplasms but rarely in normal epithelia. Comethylation of these genes is common, and pursuit of complementary markers for methylation-negative neoplasms is a rational strategy to optimize screening sensitivity.

Original languageEnglish (US)
Pages (from-to)2686-2696
Number of pages11
JournalCancer Epidemiology Biomarkers and Prevention
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2007

Fingerprint

Bone Morphogenetic Protein 3
Methylation
Adenoma
Homeobox Genes
Vimentin
Genes
Neoplasms
Epithelium
Colorectal Neoplasms
Neoplasms by Site
Cell Line
Bone Neoplasms
Mutation
Early Detection of Cancer
Colonic Neoplasms
Area Under Curve
Gene Expression

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Zou, H., Harrington, J. J., Shire, A. M., Rego, R. L., Wang, L., Campbell, M. E., ... Ahlquist, D. A. (2007). Highly methylated genes in colorectal neoplasia: Implications for screening. Cancer Epidemiology Biomarkers and Prevention, 16(12), 2686-2696. https://doi.org/10.1158/1055-9965.EPI-07-0518

Highly methylated genes in colorectal neoplasia : Implications for screening. / Zou, Hongzhi; Harrington, Jonathan J.; Shire, Abdirashid M.; Rego, Rafaela L.; Wang, Liang; Campbell, Megan E.; Oberg, Ann L; Ahlquist, David A.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 16, No. 12, 01.12.2007, p. 2686-2696.

Research output: Contribution to journalArticle

Zou, H, Harrington, JJ, Shire, AM, Rego, RL, Wang, L, Campbell, ME, Oberg, AL & Ahlquist, DA 2007, 'Highly methylated genes in colorectal neoplasia: Implications for screening', Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 12, pp. 2686-2696. https://doi.org/10.1158/1055-9965.EPI-07-0518
Zou, Hongzhi ; Harrington, Jonathan J. ; Shire, Abdirashid M. ; Rego, Rafaela L. ; Wang, Liang ; Campbell, Megan E. ; Oberg, Ann L ; Ahlquist, David A. / Highly methylated genes in colorectal neoplasia : Implications for screening. In: Cancer Epidemiology Biomarkers and Prevention. 2007 ; Vol. 16, No. 12. pp. 2686-2696.
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