Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression

Abstract

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects through a prospective 10-year study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as small clonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of somatic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident "pseudoantralized" subtype associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression.

A spatially mapped gene expression signature for intestinal stem-like cells identifies high-risk precursors of gastric cancer

“…Duodenum transit-amplifying cells, an undifferentiated population transitioning between stem cells and differentiated intestinal cells, showed reduced expression of OLFM4 , reduced expression CPS1, and expression of DMBT1 , an established marker that has been noted in other reports. 34,44…”

“…A recent longitudinal study from a Singaporean consortium also found changes in the intestinal stem-like cell compartment to be associated with risk for GC. 46 In addition, another recent report demonstrated phenotypic mosaicism in GIM, by which individual GIM cells co-express both intestinal and gastric markers. 47 This interesting finding strongly suggests that the intestinal cells identified by our studies also possess gastric transcriptional properties, substantiating the terminology of “gastric enterocytes” or “gastric intestinal stem-like cells”.…”

“…However, a recent report in lung cancer suggests that CPS1 may be crucial for pyrimidine maintenance and DNA synthesis in KRAS mutant cells. 50 Notably, KRAS was one of the driver oncogenes previously identified, 46 suggesting that there may be a relevant and novel role for CPS1 as a source supply of pyrimidines in the context of DNA synthesis among replicating precancerous cells.…”

“…Most prior molecular and genomic studies of the GIM microenvironment have focused on populations with moderate-to-high Hp prevalence and high GC incidence. 22,46,57 Our study addresses a gap in the literature by providing needed mechanistic data on advanced GIM in a relatively low-risk population common to many regions of North America and Europe. An additional motivation for developing an Hp-negative biomarker is that almost all patients diagnosed with GIM have already undergone Hp eradication therapy — that is to say, by the time such patients come to clinical attention they are functionally Hp negative.…”

“…The ongoing carcinogenic potential of Hp-negative GIM may in part be explained to the establishment of clonal stem-like cell lineages, as suggested by this and other studies. 46,57…”