Gastric tumors can arise from a single mutation in a single stomach gland, according to Lydia Gutierrez-Gonzalez et al. in the April issue of Gastroenterology.
To study how gastric dysplasias form and expand, Gutierrez-Gonzalez et al. analyzed 23 samples of gastric epithelium from patients who received surgery for gastric adenocarcinoma or high-grade dysplasia. They performed laser-capture microdissection of glands of different phenotypes, along with histochemical and genetic analyses.
Dysplasias appeared to arise from a single mutated intestinal metaplastic gland that expanded to form an entire dysplastic lesion. Within this clonal dysplastic field, genetic diversity could later arise—through loss of heterozygosity or additional mutations. Gutierrez-Gonzalez et al. concluded that gastric cancer develops through genetic progression of a subclone that arises from a founder mutation.
The authors propose that when a gene that encodes a tumor suppressor is mutated in an intestinal metaplastic gland, the gland quickly becomes dysplastic and expands to form a clonal field of dysplasia. These fields can promote the development of additional genetic abnormalities that result in multiple independent subclones. Gutierrez-Gonzalez et al. noted that this process does not seem to be universal but might be one of several mechanisms of gastric carcinogenesis.
“One single mutated, metaplastic gland is able to form the entire dysplastic lesion in the stomach. We believe this is the first step to understanding the genetic progression of metaplasia to gastric cancer” says the senior author of the study, Stuart A. C. McDonald, in a video abstract that accompanied the article.
The authors added that although the specific mutations found in dysplasias were limited, they do not think that there is a specific order of mutations in the metaplasia–dysplasia sequence.
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Gutierrez-Gonzalez L, Graham TA, Rodriguez-Justo M, et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 2011;140:1251–1260.e6.