Spatially defined microsatellite analysis reveals extensive genetic mosaicism and clonal complexity in intestinal metaplastic glands

Intestinal metaplasia (IM) has been recognized as the first irreversible precancerous stage of intestinal-type gastric cancer at which genetic instabilities, such as microsatellite (MS) instability and loss of heterozygosity, can already be detected. However, the extent and clonal relationship of these genetic lesions in the precancerous tissues are not fully appreciated. In this work, we have used well established MS markers to analyze the relatedness of spatially separated individual metaplastic glands as well as subsegments within single glands from the same patients. We found that individual IM glands frequently show different marker lengths even for closely apposed IM glands, suggesting that these tissues have already gained the ability to independently evolve their genome regardless of whether or not they share a common origin. Furthermore, within individual IM glands, there is also significant intra-gland diversity in the MS markers. Since most of these cells are not dividing and only have a limited lifespan, this result indicates that in each IM gland, a single dominant clone is rare and new clones are constantly created by either progenitor cells or stem cells. This greatly enhanced ability to create de novo genetic alterations may underlie the importance of this stage in the eventual progression toward cancer. Given the widely observed phenotype switch in the early stages of many solid tumors, whether this associated genetic stability is also an intrinsic property of metaplastic transformation should be extensively characterized to further our understanding of cancer initiation.