Morphologic and molecular analysis of early‐onset gastric cancer

Abstract

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 nextgeneration sequencing data. RESULTS: A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (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 a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. CONCLUSIONS: 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. 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. Cancer 2021;127:103-114.

Gastrointestinal Adenocarcinoma Incidence and Survival Trends in South Australia, 1990–2017

“…Globally, there have been several reports of increasing incidence of early- or young-onset cancers [ 1 ]. These encompass a spectrum of solid organ cancers such as colorectal cancer (CRC) and adenocarcinomas of the pancreas [ 2 ], breast [ 3 ], ovary [ 4 ], oesophagus [ 5 ], and stomach [ 6 ]. Though CRC has demonstrated the most striking trend, similar patterns have been uncovered in other gastrointestinal adenocarcinomas.…”

Young-Onset Carcinogenesis – The Potential Impact of Perinatal and Early Life Metabolic Influences on the Epigenome

“…The term young-, or early- onset cancers ( 1 , 2 ) encompasses a spectrum of solid organ cancers occurring in individuals under the age of 40 years [although some authors extend the upper limit of the age-group to include those <50 years ( 3 )] in whom the aetiology of their cancers cannot be traced back to pre-existing familial cancer syndromes ( 4 – 6 ). This entity has been reported to affect nearly every solid organ including the pancreas ( 7 ), breast ( 8 ), ovarian ( 5 ), oesophageal ( 9 ), colorectal ( 10 , 11 ), and gastric ( 12 ) cancer, amongst others. The large number of reports on the rising incidence of this entity from around the world ( 3 , 13 – 15 ) have left oncologists questioning the cause for the cancers and their disturbing trend.…”

A Distinct Clinicopathological Feature and Prognosis of Young Gastric Cancer Patients Aged ≤ 45 Years Old

“…However, studies have found that there are also CDH1 germline mutations in EOGC (30,31). Integrative genomic analysis found that higher proportions of early-onset diffuse gastric cancers (DGCs) contain somatic mutations in CDH1 which were associated with shorter survival times compared with late-onset DGCs (32)(33)(34). Interestingly, no clear CDH1 variants were found in Brazilian EOGC patients, and eating habits may be related to the development of EOGC (35).…”