Abstract
BackgroundThere is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh1 and Trp53 double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. However, a genomic profile of this mouse model has yet to be completed.MethodsWhole-genome sequences of tumors from eight DCKO mice were analyzed and their molecular features were compared with those of human gastric adenocarcinoma.ResultsDCKO mice gastric cancers harbored single nucleotide variations and indel patterns comparable to those of human genomically stable gastric cancers, whereas their copy number variation fraction and ploidy were more similar to human chromosomal instability gastric cancers (perhaps due to Trp53 knockout). Copy number variations dominated changes in cancer-related genes in DCKO mice, with typical high-level amplifications observed for oncogenic drivers, e.g., Myc, Ccnd1, and Cdks, as well as gastrointestinal transcription factors, e.g., Gata4, Foxa1, and Sox9. Interestingly, frequent alterations in gastrointestinal transcription factors in DCKO mice indicated their potential role in tumorigenesis. Furthermore, mouse gastric cancer had a reproducible but smaller number of mutational signatures than human gastric cancer, including the potentially acid-related signature 17, indicating shared tumorigenic etiologies in humans and mice.ConclusionsCdh1/Trp53 DCKO mice have similar genomic features to those found in human gastric cancer; hence, this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies.
Highlights
Gastric cancer (GC) is the fifth most prevalent cancer and ranks third in cancer deaths globally; incidence varies among regions, but is highest in eastern Asia [1, 2]
Cdh1/Trp53 double conditional knockout (DCKO) mice have similar genomic features to those found in human gastric cancer; this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies
Our results suggest that this DCKO mouse is genetically comparable to human GC and is considered an appropriate diffuse-type GC (DGC) model mouse for further investigation
Summary
Gastric cancer (GC) is the fifth most prevalent cancer and ranks third in cancer deaths globally; incidence varies among regions, but is highest in eastern Asia [1, 2]. There is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh and Trp double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. Conclusions Cdh1/Trp DCKO mice have similar genomic features to those found in human gastric cancer; this is a suitable model for further studies of diffuse-type gastric cancer mechanisms and therapies
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