DNA hypermethylation in the normal colonic mucosa of patients with colorectal cancer

被引:112
作者
Kawakami, K
Ruszkiewicz, A
Bennett, G
Moore, J
Grieu, F
Watanabe, G
Iacopetta, B [1 ]
机构
[1] Univ Western Australia, Sch Surg & Pathol, Nedlands, WA 6009, Australia
[2] Kanazawa Univ, Sch Med, Dept Surg, Kanazawa, Ishikawa 9208641, Japan
[3] Inst Med & Vet Sci, Div Tissue Pathol, Adelaide, SA 5000, Australia
[4] Royal Adelaide Hosp, Colorectal Unit, Adelaide, SA 5000, Australia
关键词
ER alpha; MYOD; promoter methylation; DNMT3b; polymorphism; ageing;
D O I
10.1038/sj.bjc.6602940
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The CpG-island methylator phenotype (CIMP+) in colorectal cancer (CRC) is characterised by frequent hypermethylation of promoter regions in tumour suppressor genes. Low level methylation of some CpG islands is also seen in the normal colonic mucosa and increases with age; however, it is still unclear what other factors regulate this phenomenon. The first aim of our study was to determine whether the level of promoter methylation is elevated in the normal colonic mucosa of patients with CIMP+ tumours. The second aim was to investigate whether common, functional polymorphisms in genes involved in methyl group metabolism are associated with the level of methylation in this tissue. CpG islands within the ER alpha, MYOD, P16(INK4A), MLHI, APC, P14(ARF), DAPK and TIMP3 genes were quantitatively evaluated for methylation in normal colonic mucosa from a large series of CRC patients using the MethyLight assay. Genotyping was carried out for polymorphisms in the MTHFR, TS, MS, MTHFDI and DNMT3b genes. Methylation of ERa and MYOD in normal colonic mucosa increased with age and was higher in female subjects. Methylation of P16( INK4A), MLHI, TIMP3 and DAPK in normal mucosa occurred at a lower level than ERa and MYOD but also increased with age and was significantly higher in patients with CIMP+ tumours. The DNMT3b C46359T polymorphism was associated with significantly less methylation of MYOD and MLHI and with trends for lower methylation in each of the other CpG islands examined. Our results demonstrate that age, gender and genetic factors can influence the methylation level of CpG islands in gene promoter regions of normal colonic mucosa. Further work is required to determine whether such methylation is associated with the development of CIMP+ CRC.
引用
收藏
页码:593 / 598
页数:6
相关论文
共 40 条
  • [1] Ahuja N, 1998, CANCER RES, V58, P5489
  • [2] The relationship between hypomethylation and CpG island methylation in colorectal neoplasia
    Bariol, C
    Suter, C
    Cheong, K
    Ku, SL
    Meagher, A
    Hawkins, N
    Ward, R
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2003, 162 (04) : 1361 - 1371
  • [3] Baylin SB, 1998, ADV CANCER RES, V72, P141
  • [4] Polymorphisms in the one-carbon metabolic pathway, plasma folate levels and colorectal cancer in a prospective study
    Chen, J
    Kyte, C
    Valcin, M
    Chan, W
    Wetmur, JG
    Selhub, J
    Hunter, DJ
    Ma, J
    [J]. INTERNATIONAL JOURNAL OF CANCER, 2004, 110 (04) : 617 - 620
  • [5] Folate status: Effects on pathways of colorectal carcinogenesis
    Choi, SW
    Mason, JB
    [J]. JOURNAL OF NUTRITION, 2002, 132 (08) : 2413S - 2418S
  • [6] Eads CA, 2001, CANCER RES, V61, P3410
  • [7] HYPOMETHYLATION DISTINGUISHES GENES OF SOME HUMAN CANCERS FROM THEIR NORMAL COUNTERPARTS
    FEINBERG, AP
    VOGELSTEIN, B
    [J]. NATURE, 1983, 301 (5895) : 89 - 92
  • [8] Frazier ML, 2003, CANCER RES, V63, P4805
  • [9] Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer
    Frigola, J
    Solé, X
    Paz, MF
    Moreno, V
    Esteller, M
    Capellà, G
    Peinado, MA
    [J]. HUMAN MOLECULAR GENETICS, 2005, 14 (02) : 319 - 326
  • [10] A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status
    Friso, S
    Choi, SW
    Girelli, D
    Mason, JB
    Dolnikowski, GG
    Bagley, PJ
    Olivieri, O
    Jacques, PF
    Rosenberg, IH
    Corrocher, R
    Selhub, J
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (08) : 5606 - 5611