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Early Gastric Cancer Signature Identified in Single-Cell Transcriptome Study

NEW YORK (GenomeWeb) – Researchers have constructed a single-cell transcriptome atlas showing network changes that occur during the progression from precancerous lesions to early gastric cancer.

The team, led by Tsinghua University's Shao Li, performed RNA sequencing on more than 32,000 single cells from individuals with gastritis, premalignant gastric lesions, and early gastric cancer. They uncovered variations in gene expression along the continuum of cells from premalignant to early-malignant lesions and noted, for instance, that gland mucosal cells appeared to develop an intestinal-like stem cell phenotype as disease progresses. Additionally, the researchers identified a signature specific to early gastric cancer, which they said could help diagnose the condition.

"[W]e speculated that single-cell sequencing technology may provide a high-resolution method for the identification of molecular markers for use in precisely detecting early neoplastic sites and the onset of rare neoplastic cells in the clinic," Li and his colleagues wrote in their paper, which appeared today in Cell Reports.

The researchers collected 13 biopsies from nine individuals with non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, or early gastric cancer. Two of the patients, though not the others, were infected with Helicobacter pylori. They then isolated single cells from each biopsy for RNA sequencing, and after quality control checks, they analyzed 32,332 cells.

Using dimensionality reduction and clustering based on the cells' gene expression patterns, the researchers uncovered 17 main clusters within these cells. They noted that the cells' profiles fell broadly along the cascade from premalignant to early cancer cells.

The researchers particularly focused on the changes that took place within epithelial cells along the path from gastritis to gastric cancer. By examining associations between pairs of epithelial cell types, they developed a single-cell transcriptomic network that they said provides a systematic look at the spectrum of premalignant and early cancer lesions.

Based on this network, the researchers found that the gastric mucous-secreting cell type is conserved across lesion types, and mostly consists of MUC5AC-expressing pit mucous cells and MUC6-expressing antral basal gland mucous cells, each of which has its own gene expression patterns. Pit mucous cells expressed genes involved in actin cytoskeleton and bacterial invasion, while antral basal gland mucous cells expressed genes involved in the immune response.

 They noted a further division among MUC6-expressing cells that grouped them into subclusters, one of which is enriched for immune-related genes and the other enriched for stem cell- or development-related genes. The observation that OLFM4 expression increased among these cells as MUC6 expression declines led the researchers to suggest that gland mucous cells acquire a stem cell-like phenotype, which could be a key step in tumorigenesis.

Meanwhile, they identified genes whose expression appears to mark certain cell types. For instance, they reported that OR51E1 appears to be a marker for early gastric cancers' endocrine cell lineage, while HES6 appears to mark early goblet cells, including ones that don't yet have all the morphological markers of goblet cells. This, they said, might help identify patients at high risk of developing gastric cancer.

Similarly, using their network, the researchers uncovered a set of six genes — including KLK10, SLC11A2, and ECM1 — whose expression appears to identify early gastric cancer cells. This signature, they added, could be used to identify patients whose disease is in its early stages.

"With the atlas, we characterized the expression patterns of diverse cell types in each lesion and analyzed their changes across lesions," Li and his colleagues wrote. "Of note, we identified a panel of early neoplastic cell-specific marker genes, providing a molecular basis to precisely diagnose" early gastric cancer.