Mutational Landscape of Gastric Adenocarcinoma of the Fundic Gland Type Revealed by Whole Genome Sequencing

Abstract

ABSTRACT Background Gastric adenocarcinoma of the fundic gland type (GA‐FG) is a newly described variant of gastric adenocarcinoma with lack of knowledges regarding its genetic features. Methods We performed whole‐genome sequencing (WGS) in formalin‐fixed paraffin‐embedded (FFPE) tumor tissues and matched adjacent noncancerous specimens from 21 patients with GA‐FG, and integrated published datasets from 1105 patients with traditional gastric adenocarcinoma with the purpose of dissecting genetic determinants both common to conventional gastric adenocarcinoma and unique to GA‐FG disease. Results We characterized the genomic architecture of GA‐FG disease, revealing the predominant proportion of C > T substitution among the six types of SNVs. GNAS was the most significantly mutated driver gene (14.29%). 42.8% of samples harbored “Kataegis.” Distinct genomic alterations between GA‐FG and conventional gastric cancer were identified. Specifically, low mutational burden and relatively moderate mutational frequencies of significantly mutated driver genes, coupled with the absence of non‐silent alterations of formerly well‐known drivers such as TP53, PIK3CA and KRAS were identified in GA‐FG patients. Oncogenic signaling pathway analysis revealed mutational processes associated with focal adhesions and proteoglycans in cancer, highlighting both common and specific procedures during the development of GA‐FG and conventional gastric cancer. Conclusion Our study is the first to comprehensively depict the genomic landscape highlighting the multidimensional perturbations in GA‐FG patients. These discoveries offered mechanistic insights for novel diagnostic and therapeutic strategies for patients with such disease.

Keywords

• gastric adenocarcinoma
• gastric adenocarcinoma of the fundic gland type
• GNAS
• mutational landscape
• whole genome sequencing