DNA methylation, field effects, and colorectal cancer.

EDITORIALS 1317 The concept of fi eld effect was fi rst introduced by Slaughter et al. ( 1 ) in 1953, when they studied the presence of histologically abnormal tissue surrounding oral squamous cell carcinoma. This concept, also called fi eld defect or fi eld cancerization, was proposed to explain the development of multiple primary tumors in the same organ and locally recurrent cancer. Field effects are considered to underlie the multicentricity of cancer in many, if not all, patients who have multiple tumors in the same organ but no apparent familial predisposition to those tumors. In the multistep carcinogenesis model proposed by Fearon and Vogelstein ( 2 ) , genetic alterations occur in a stepwise fashion such that a clone that has growth advantage proliferates, acquires more genetic alterations, and undergoes another selection for survival and growth, eventually resulting in cancer. According to this model, precancerous cells that are in proximity to cancer cells should have at least some, but not all, of the genetic alterations that are present in the fully developed cancer. In support of this model are observations of genetic alterations in fi elds of precancerous cells in a variety of organs, including lung ( 3 ) , esophagus ( 4 ) , vulva ( 5 ) , cervix ( 6 ) , and urinary tract ( 7 ) . Alterations in DNA methylation patterns may also potentially contribute to fi eld effects ( 8 ) . Aberrant DNA methylation has been demonstrated in a variety of tissues, including in esophageal mucosa in Barrett’s esophagus ( 8 ) , in colonic mucosa affected by ulcerative colitis ( 9 ) , in normal-appearing bladder mucosa ( 10 ) , in normal-appearing gastric mucosa ( 11 ) , and in normal-appearing bronchus in lung cancer resection specimens ( 12 ) . In this issue of the Journal, Shen et al. ( 13 ) describe methylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene promoter in normal-appearing colorectal mucosa adjacent to colorectal cancer. The authors demonstrated that normalappearing mucosa located 1 cm away from a colorectal cancer with MGMT promoter methylation was more likely to also have hypermethylation and possibly a higher degree of methylation than normal-appearing colorectal mucosa located 10 cm away from the same colorectal cancer, thus providing evidence for fi eld effects due to DNA methylation in normal-appearing colonic mucosa. These data also indicate that MGMT promoter methylation might occur early in multistep carcinogenesis, even before the emergence of morphologic changes in colorectal mucosa. The biologic consequence of loss of MGMT expression through hypermethylation is that the MGMT protein removes mutagenic adducts from the O 6 -guanine base residue in DNA. When left unrepaired, O 6 -methylguanine is read by DNA polymerase as adenine, resulting in a G-to-A transition ( 14 , 15 ) . MGMT gene silencing by promoter hypermethylation occurs in 20% – 40% of colorectal cancers ( 16 ) and has been associated with an increase in G-to-A mutations in the KRAS and TP53 genes in colorectal tumors ( 17 , 18 ) . The study by Shen et al. ( 13 ) raises several important issues and potential implications. The authors suggest that the discovery EDITORIALS