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Gastric Cancer Driver Analysis Leads to Ancestry-, Subtype-Specific Features

NEW YORK – A team from Japan and Singapore has characterized recurrently altered genes in gastric cancer, including potential driver genes and alterations associated with gastric cancers that turn up in East Asian patients with a history of alcohol consumption.

"Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries," senior and corresponding author Tatsuhiro Shibata, a cancer genomics and molecular medicine researcher affiliated with the National Cancer Center Research Institute and the University of Tokyo, and his colleagues wrote in Nature Genetics on Monday.

As part of the International Cancer Genome Consortium (ICGC)'s Accelerating Research in Genomic Oncology initiative, researchers at the University of Tokyo and elsewhere assessed genomic data for more than 1,400 gastric cancer samples from the Cancer Genome Atlas and other cohorts from China, Korea, Singapore, and Vietnam, along with new whole-genome sequence, exome sequence, RNA sequence, and/or array-based methylation data on samples from 697 gastric cancer cases from Japan.

"In the present study, we report the findings from a large number of gastric cancer cases and elucidate the molecular alterations and carcinogenic processes associated with gastric cancer heterogeneity," the authors explained, noting that the latest results "provide insights into the ancestry-dependent landscape of driver events in gastric cancer."

From the 77 significantly mutated genes flagged in the study, the team focused in on dozens of candidate gastric cancer driver genes — roughly three more than reported in previous analyses from the Cancer Genome Atlas project, Shibata noted in an email. Among them were gastric cancer drivers that seemed to be specific to certain gastric cancer subtypes, lifestyle factors, or ancestry groups.

By digging into the "long-tail" of their mutated gene set, for example, the investigators found that recurrent hotspot changes affecting the Rho GTPase-activating protein-coding gene ARHGAP5 tended to turn up in gastric cancer tumors with high levels of EGFR gene amplification.

On the other hand, the available transcriptome data highlighted gene fusions involving Rho GTPase-activating proteins that tended to turn up in tumors from the diffuse gastric cancer subtype that were missing mutations in ARHGAP5 or other Rho GTPase pathway-related genes.

Tumors from the diffuse subtype were also more apt to contain alterations affecting genes such as PIGR, CDH1, or SOX9, the team reported, while the intestinal gastric cancer subtype more often contained mutations involving genes from receptor tyrosine kinase/RAS signaling pathways or cell cycle-related pathways.

When they explored mutational signatures in the gastric cancers, meanwhile, the researchers saw ties between alcohol consumption, ALDH2 germline variants, and a Y42C somatic hotspot mutation affecting the Rho family small GTPase enzyme-coding gene RHOA in gastric cancer patients of East Asian ancestry — particularly those with tumors from the diffuse subtype.

"These results imply that the mutational processes generating RHOA Y42C hotspot mutations are influenced by the combination of ALDH2 … genotypes and alcohol consumption," the authors wrote, suggesting that those with a particular ALDH2 genotype "could be at risk for developing diffuse-type gastric cancer and be a potential target of preventive intervention," such as reducing alcohol consumption and undergoing intensive endoscopic screening.

In addition, the team's ancestry-focused analyses also pointed to potential differences in tumor location and mutation patterns in the East Asian and European cases, including distinct driver gene patterns, underlying germline risk factors, and an overrepresentation of hypermutated tumors in European ancestry patients.

"We compared the gastric cancer genomes of Caucasian and East Asian patients and discovered unique genetic features in both ethnic groups," Shibata said.