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Abstract

We thank Drs Gonzalez-García and Castells for their commentary on our paper (Cancer cell, 2006;9:199–207). We have little to add, but we appreciate the opportunity we have been given to highlight the interesting difference between the genetic and epigenetic alterations observed in gastrointestinal cancer. Although somatic mutations must be present in normal tissues, they are not reproducibly found by the techniques used for mutational analyses. This means that mutations must be very rare. If they are nonfunctional, they remain undetectable, confined to a few normal cells in the intestinal epithelium. If they contribute to neoplastic or malignant transformation (for instance, APC, K-ras), then, the normal tissue cells where they occur do not stay normal for long. By contrast, epigenetic alterations (both DNA hypermethylation and hypomethylation) are frequently detected in normal tissues adjacent to tumors. This means that they must occur with relatively high frequency, thereby allowing for clonal expansion of normal cells harboring these alterations in their natural life spans. The intestinal epithelium is a tissue with very high cell turnover, continuously replenished by self-renewing stem cells. During aging, the destruction of stem cells in the intestinal crypts entails a necessary expansion of larger patches of normal tissue derived from the same single stem cells. Detection of epigenetic alterations accumulating with aging is thus possible, especially when sensitive techniques are used. Whether these epigenetic alterations occur in the normal tissues of all people or only cancer patients remains to be determined. In this context, our unpublished results show the accumulation of global demethylation in normal gastric tissues adjacent to gastric cancers, and in normal tissues of cancer-risk chronic gastritis patients, compared with the normal tissues from cancer-free individuals. We also wish to correct Drs González-García and Castells in their citation of our past work “…Ionov et al (Nature 1993;363:558–561) showed that some tumors accumulated hundreds or thousands of somatic mutations in microsatellite sequences. …” We reported the existence of hundreds of thousands of somatic, clonal mutations in these tumors. It may be a typographical error, but does make a big difference. Finally, our only disagreement with González-García and Castells is with the last sentence of their commentary “More studies are needed to clarify this controversial [CIMP] issue.” We disagree that the CIMP issue is controversial. Although more DNA methylation experiments are necessary regarding many important issues (see above), we do not think there are more needed regarding the CIMP issue. The CIMP story is a fascinating example of how untenable hypotheses can be perpetuated in the absence of supporting evidence. It is fascinating, because the concept is defended by converted followers of the hypothesis despite being in contradiction with each other (Nat Genet 2006;38:787–793; Gastroenterology 2007;132:127–138), even when the original proponents hauled down the sails (“The controversy over CIMP will almost certainly one day be considered a storm in a tea pot,” Gastroenterology 2005;129:1121–1124). A methylator phenotype implies the existence of underlying methylator genes. Eight years after the original proposal of the CIMP hypothesis (Proc Natl Acad Sci U S A 1999;96:8681–8686), we are still waiting to know where and what the methylator genes are. New Insights into a Controversial Topic: The Methylation–Cancer ConnectionGastroenterologyVol. 132Issue 5PreviewSuzuki K, Suzuki I, Leodolter A, Horiuchi S, Yamashita K, Perucho M (Burnham Institute for Medical Research, Cancer Genetics and Epigenetics Research Program, La Jolla, CA). Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell 2006;9:199–207. Full-Text PDF