Enrichment of Smooth Muscle Signature in Gastric Cancer Is Associated with Low Burden of Genomic Aberrations and Poor Survival

Abstract

Background: Bormann IV gastric cancer (B-IV GC) is characterized by stealth tumor growth and invasion of cancer cells into the stomach wall. It is also associated with very poor prognosis. The molecular mechanism of Bormann IV gastric cancer is still unclear. Methods: In this study, we compare the mRNA expression profiles between Borrman IV and non-Borrmann IV gastric cancer to find out differences in gene expression with GEO dataset. Then we validated our findings using TCGA gastric cancer dataset. Results: We found that B-IV gastric cancer had a distinct gene expression pattern. The smooth muscle geneset was highly enriched in B-IV gastric cancer, and was associated with low tumor purity. Using this smooth musclegeneset, we classified GC into smooth muscle enriched and non-enriched groups. Notably, enrichment of smooth muscle was associated with both poor disease free survival and overall survival. A B-IV GC signature was derived by comparing gene expression of B-IV and non-B-IV gastric cancers. Analysis of RNA sequencing data from TCGA gastric cancer study revealed a similar subgroup of tumors that showed gene expression patterns B-IV GC. This group of tumors mainly came from the genome stable (GS) molecular subtype. More importantly, these tumors were associated with higher CDH1 mutation rate, but lower overall tumor mutation burden and copy number variation burden. Conclusions: In conclusion, Borrmann IV gastric cancer tissue is characterized by smooth muscle gene expression pattern and low tumor purity, and the seemly stable genome of these tumors may not reveal their true genomic background. Funding Statement: This study was supported by International Program for Ph.D. Candidates from Sun Yat-sen University. This work was also Supported by the Natural Science Foundation of Guangdong Province, China (No. 2016A030310155, 2016A020213002) and National Natural Science Foundation of China (No. 81602049). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All procedures were in accordance with the institutional ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients for being included in the study by the original investigators.