Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study

Abstract

Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

Keywords: DNA mismatch repair; early onset cancer; familial cancer; gastric cancer; hereditary cancer.

Figure 1

Immunohistochemistry of DNA mismatch repair proteins (MMR-IHC) in gastric cancer tissue loss of protein expression of MLH1 and PMS2, and normal protein expression of MSH2 and MSH6.

Figure 2

Scheme followed summarizing the results of IHC-MMR and germline genetic testing.

Figure 3

Overall survival rate based on diagnostic stage (stage I–II vs. stage III–IV). There is a significant difference in the 5-year survival rate: stage I–II 87% vs. stage III–IV 11.3%, p = 0.0001.