Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations

Abstract

The prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming "H. pylori-negative era."

Fig. 1

Future perspectives for gastric cancer (GC) in east Asia in the upcoming H. pylori-negative era. Schematic summary of this review article. State-of-the-art somatic and germline genetic analyses have clarified the precise molecular pathology of gastric carcinogenesis (left). Based on such knowledge of the genetics of GC in the current era, the future perspectives for new types of GC in the H. pylori-negative era are speculated (right). Graphs of the mutational signatures are derived from COSMIC website (Mutational Signatures v2, https://cancer.sanger.ac.uk/cosmic/signatures_v2.tt)

Fig. 2

Mutational signatures in the cancer genome. The somatic mutation profile in an individual gastric cancer genome (center) can be mathematically factorized into cumulative combinations of mutational signatures (outer graphs). To date, more than 60 mutational signatures have been proposed by COSMIC, several of which are linked to specific carcinogenic factors (smoking, alcohol use, ultraviolet exposure, ageing, etc.). By calculating the contribution score for each mutational signature (α, β, γ, etc.), the relative contributions of the causative factors to carcinogenesis can precisely be estimated. Graphs of the mutational signatures are derived from COSMIC website (Mutational Signatures v2, https://cancer.sanger.ac.uk/cosmic/signatures_v2.tt)

Fig. 3

Germline variants in CDH1 gene identified in GC patients. A histogram of non-silent germline variants of CDH1 gene identified in a recent trans-ethnic study [32]. Colors of the circles represent ethnicities of the patients as indicated. Circles with black rims represent cases of DGC. * and # represent CDH1 variants that were predicted as damaging in silico and found in clinical HDGC families, respectively