Suzuki Hiromu, Gabrielson Edward, Chen Wei, Anbazhagan Ramaswamy, van Engeland Manon, Weijenberg Matty P, Herman James G, Baylin Stephen B
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, Maryland 21231, USA.
Nat Genet. 2002 Jun;31(2):141-9. doi: 10.1038/ng892. Epub 2002 May 6.
Aberrant hypermethylation of gene promoters is a major mechanism associated with inactivation of tumor-suppressor genes in cancer. We previously showed this transcriptional silencing to be mediated by both methylation and histone deacetylase activity, with methylation being dominant. Here, we have used cDNA microarray analysis to screen for genes that are epigenetically silenced in human colorectal cancer. By screening over 10,000 genes, we show that our approach can identify a substantial number of genes with promoter hypermethylation in a given cancer; these are distinct from genes with unmethylated promoters, for which increased expression is produced by histone deacetylase inhibition alone. Many of the hypermethylated genes we identified have high potential for roles in tumorigenesis by virtue of their predicted function and chromosome position. We also identified a group of genes that are preferentially hypermethylated in colorectal cancer and gastric cancer. One of these genes, SFRP1, belongs to a gene family; we show that hypermethylation of four genes in this family occurs very frequently in colorectal cancer, providing for (i) a unique potential mechanism for loss of tumor-suppressor gene function and (ii) construction of a molecular marker panel that could detect virtually all colorectal cancer.
基因启动子的异常高甲基化是癌症中与肿瘤抑制基因失活相关的主要机制。我们之前表明这种转录沉默是由甲基化和组蛋白去乙酰化酶活性共同介导的，其中甲基化起主导作用。在此，我们利用cDNA微阵列分析来筛选在人类结直肠癌中发生表观遗传沉默的基因。通过筛选超过10000个基因，我们表明我们的方法能够在特定癌症中鉴定出大量启动子高甲基化的基因；这些基因与启动子未甲基化的基因不同，后者单独通过组蛋白去乙酰化酶抑制就能产生表达增加。我们鉴定出的许多高甲基化基因，凭借其预测功能和染色体位置，在肿瘤发生中具有很高的发挥作用的潜力。我们还鉴定出一组在结直肠癌和胃癌中优先发生高甲基化的基因。其中一个基因SFRP1属于一个基因家族；我们表明该家族中四个基因的高甲基化在结直肠癌中非常频繁地发生，这为（i）肿瘤抑制基因功能丧失提供了一种独特的潜在机制，以及（ii）构建一个几乎可以检测所有结直肠癌的分子标志物组合提供了可能。
