Origins of Gastric Cancer

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.

All dysplastic glands share a founder mutation. (A) A composite H&E of an entire strip of gastric mucosa showing intestinal metaplasia and dysplasia from patient 2 (c.4688insA in APC). (B) Higher power of highlighted areas. (C) Serial section, showing postlaser capture microdissection. The space left by the laser-capture microdissected gland has been colored to reflect the genotype. Blue filled areas are dysplastic glands positive for the c.4688insA mutation, red are positive metaplastic glands, and green are negative metaplastic glands.

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.

More Information on Gastric Cancer:

Read the article online.
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.

About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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1 Response to Origins of Gastric Cancer

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