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  • Review Article
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Mapping the genomic diaspora of gastric cancer

Abstract

Gastric cancer (GC) is a leading contributor to global cancer incidence and mortality. Pioneering genomic studies, focusing largely on primary GCs, revealed driver alterations in genes such as ERBB2, FGFR2, TP53 and ARID1A as well as multiple molecular subtypes. However, clinical efforts targeting these alterations have produced variable results, hampered by complex co-alteration patterns in molecular profiles and intra-patient genomic heterogeneity. In this Review, we highlight foundational and translational advances in dissecting the genomic cartography of GC, including non-coding variants, epigenomic aberrations and transcriptomic alterations, and describe how these alterations interplay with environmental influences, germline factors and the tumour microenvironment. Mapping of these alterations over the GC life cycle in normal gastric tissues, metaplasia, primary carcinoma and distant metastasis will improve our understanding of biological mechanisms driving GC development and promoting cancer hallmarks. On the translational front, integrative genomic approaches are identifying diverse mechanisms of GC therapy resistance and emerging preclinical targets, enabled by technologies such as single-cell sequencing and liquid biopsies. Validating these insights will require specifically designed GC cohorts, converging multi-modal genomic data with longitudinal data on therapeutic challenges and patient outcomes. Genomic findings from these studies will facilitate ‘next-generation’ clinical initiatives in GC precision oncology and prevention.

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Fig. 1: Discovery of non-coding genomic alterations, epigenetic modifications and RNA alterations in GC.
Fig. 2: Temporal evolution of GCs from pre-malignancy to metaplasia and carcinoma.
Fig. 3: Precision prevention strategies for GC.

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Acknowledgements

K.G.Y. and P.T. thank H. Grabsch, Z. Xiao, R. Sundar, N. Padmanabhan, G. Lin and Tan laboratory members for assistance in manuscript preparation. This work was supported by Singapore Ministry of Health National Medical Research Council grant NMRC/STaR/0026/2015, Bedside & Bench grant (NMRC/BnB/0014b/2014), Open Fund-Large Collaborative Grant MOH-OFLCG-18May-0003 and the National Research Foundation, Singapore.

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Correspondence to Patrick Tan.

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P.T. declares ownership of patents related to alternate promoter utilization in cancer covered under the Agency for Science, Technology, and Research. Y.K.G. declares ownership in patents related to miRNA blood tests for gastric cancer.

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Glossary

Helicobacter pylori

A bacterium capable of living in the stomach and associated with increased gastric cancer risk.

Stroma

Cell types present in a tumour but not cancer epithelial cells, such as fibroblasts, blood vessels and immune cells.

Driver gene

A gene where mutations functionally contribute to the development of cancer.

Chromosomal instability

(CIN). Defective control of chromosomal number and structure.

Microsatellite instability

(MSI). Defective replication of specific repeat-regions (microsatellites) in the genome.

Metachronous cancers

Cancers that occur 6 months after resection of the primary cancer.

Clones

Set of cells with shared genetic traits among a larger field of cells.

IHC3+

A measure of the intensity of immunohistochemical staining (3+: high; 2+ moderate; 1+ weak).

Covariates

Factors that directly or indirectly influence the variable of interest.

Chromatin modifications

Chemical modifications occurring at precise positions in DNA–protein complexes and necessary for gene regulation.

Topologically associated domains

(TADs). Three-dimensional chromatin domains involved in regulating gene expression.

Tandem duplications

(TDs). A mutational process where genomic regions are copied adjacent to one another.

Enhancer

A non-coding region of the genome that can activate the expression of target genes.

Homologous recombination

A repair process where double-stranded DNA breaks are corrected using similar or identical DNA molecules in the cell.

Polygenic risk scores

(PRSs). A number comprising the weighted aggregate of multiple genetic variants associated with a particular phenotype.

Peritoneal carcinomatosis

(PC). A condition where tumour cells from the primary tumour are shed into the peritoneal cavity.

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Yeoh, K.G., Tan, P. Mapping the genomic diaspora of gastric cancer. Nat Rev Cancer 22, 71–84 (2022). https://doi.org/10.1038/s41568-021-00412-7

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