Dr Hiroyuki MANO National Cancer Center Japan Link to biosketch

Abstract

Scirrhous-type (or linitis plastica-type) gastric cancer (SGC) is one of the most fatal malignancies with frequent manifestation of peritoneal dissemination at early clinical stages. Genomics analyses of SGC have been hampered by its low tumor contents in cancer specimens. To identify targetable vulnerabilities of SGC, we purified cancer cells from malignant ascitic fluid and also established cell lines from a total of 98 patients with gastric cancer. Interestingly, about 70% of them had peritoneal metastasis as the first distant metastatic site. Another 20% of the patients had a pathological subtype of signet-ring cell/poorly differentiated cancer cells. Therefore, more than 90% of the individuals can be clinically estimated as SGC.

All those specimens were subjected to whole-genome sequencing, RNA-seq, genome-wide methylation analyses, and ChIP-seq for H3K27ac. On the contrary to the genomic character of diffuse-type gastric cancer previously reported, TP53 is the most frequently (56%) mutated gene in our SGC cohort. PIGR was also identified as a driver gene. Importantly, a high-grade amplification (mean copy number = 76) or fusion was observed in a half of the cases for the genes in the receptor-type tyrosine kinase-RAS-MAPK pathway. Treatment with corresponding kinase inhibitors resulted in cancer eradiation in a mouse model for SGC peritoneal metastases.

Hierarchical clustering of the specimens with RNA-seq data separated 40% of them with the epithelial-mesenchymal transition (EMT) phenotype from the remaining non-EMT group. The EMT group showed simultaneously a loss of CDKN2A/B and a transcriptional activation ofSMAD3 with a super-enhancer present on its locus. Interestingly, TEAD1 andWWTR1 (TAZ) were markedly expressed only in the EMT group, and the treatment with a TEAD inhibitor resulted in the growth suppression of SGC of the EMT group. Taken together, our discoveries for SGC propose a novel scheme for genome-based therapeutic strategies for this intractable malignancy.