Morphologic and molecular analysis of early-onset gastric cancer

Background Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. Methods Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. Results A higher rate ofCDH1mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers;P= .0042) but a similar rate ofTP53mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers;P= .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type;P= .027) and the presence of aCDH1gene mutation (overall survival, 9 months for mutantCDH1and 22 months for wild-typeCDH1;P= .013) significantly correlated with worse survival. TheTP53gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1andAPC) and moderate-penetrance genes (ATM,NBN, andMUTYH) in 9.9% of cancers. Conclusions Early-onset gastric cancer has distinct genomic alterations, such asCDH1mutations, but shares with traditional gastric cancers a high frequency ofTP53mutations and theTP53mutagenic signature. Diffuse and indeterminate histologic types and the presence of aCDH1mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

Automated summary

Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival.