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Gastric Cancer Analysis Uncovers Links to Alcohol Use, Genetic Factors in East Asians

NEW YORK – With a genomic analysis spanning more than 500 gastric cancer cases, a team lead by researchers at the University of Tokyo has uncovered a subset of diffuse-type gastric cancer in East Asians that appears to have both genetic and environmental risk contributors, including alcohol use.

"Approximately one-fifth of the [diffuse-type gastric cancers] in our study were attributable either to the alcohol consumption coupled with [a] defective ALDH2 allele or to the germline loss-of-function variants of CDH1," co-senior authors Hiroyuki Aburatani and Shumpei Ishikawa, both with the University of Tokyo, and their co-authors wrote in a study published in Science Advances on Wednesday.

Using exome sequencing, Aburatani, Ishikawa, and colleagues first characterized hundreds of paired tumor and matched normal samples from Japanese individuals with gastric cancer, comparing the sequences with those from nearly 300 gastric cancer cases profiled for the Cancer Genome Atlas project (TCGA).

By bringing in cancer subtype information and mutation signature clues from the COSMIC database, they saw a set of gastric cancers marked by a mutation signature known as signature 16, which has been linked to alcohol use in the presence of defects in the aldehyde dehydrogenase enzyme-coding gene ALDH2 in liver and other cancer types.

The team determined that nearly 90 percent of the gastric cancer cases with the so-called signature 16 mutation occurred in Asian individuals, prompting a series of follow-up analyses that brought in gene expression, histopathology, behavioral, and family history data. The tumors — which made up 22 of the 105 diffuse-type gastric cancers profiled in Japanese patients — tended to have relatively low mutation levels overall, for example, along with specific immune features such as B cell infiltration.

Alcohol use was not the only contributor. Both ALDH2 mutations and loss-of-function germline mutations in the E-cadherin-coding gene CDH1 appeared to contribute to the risk of developing the diffuse-type gastric cancers with signature 16, the researchers reported. They noted that germline changes to CDH1 seem to occur in more than 7 percent of the Japanese and Korean individuals, based on available sequence data.

Notably, the team saw signs that gastric cancer patients with signature 16 in their tumors did not necessarily report high levels of alcohol use, suggesting even relatively modest alcohol consumption may have an impact in individuals with a genetic predisposition for the disease.

"Although recent whole-genome/exome sequencing has contributed to the global characterization of somatic genetics and driver genes of [gastric cancers], the precise interplays among lifestyles, germline variations, and somatic mutations, especially in the contexts of ethnic variations, are not fully clarified to date," the authors explained.

On the other hand, the researchers suggested that the latest data "clarified previously unrecognized impacts of the defined germline and lifestyle factors on the high incidence of [gastric cancers] in East Asian areas, and provided us strong motivations for clinical interventions in lifestyle and familial care coupled with precision germline genotyping in these areas."