Abstract 3421: Genomic correlates of patient age in diffuse-type gastric cancer

Background: Gastric cancer is increasing in incidence among young white populations in the US. Gastric cancer in young patients is notable for its enrichment of diffuse histology as well as female predominance and aggressive clinical course, whereas gastric cancer is generally more frequent in males. Thus, clinicopathological characteristics of diffuse-type gastric cancer differ according to patient age, but the molecular mechanisms for early-onset gastric cancer's unique clinicopathological characteristics have not been elucidated. While the incidence of intestinal-type gastric cancer is decreasing worldwide, that of diffuse-type gastric cancer remained constant. Nonetheless, relatively small numbers of diffuse-type gastric cancers have been represented in whole exome sequencing studies such as TCGA project. We therefore investigated germline and somatic mutation profiles of diffuse-type gastric cancers with regards to patient age. Methods: We conducted whole exome and targeted sequencing and SNP6.0 array analyses of resected tumor tissue and blood samples collected from young (45 years old or younger) Korean patients with diffuse-type gastric cancer, and compared the genomic data with those from older Korean patients with diffuse-type gastric cancer. Genomic data of Korean diffuse-type gastric cancers were also compared with TCGA diffuse-type gastric cancers, 70% of which were from Caucasians. Results: Among 84 young Korean patients with DGC, 7 patients (8.3%) harbored germline mutations in TP53, CDH1, ATM, RAD51D, or PALB2. Three tumors with strong mutation signatures for inherited DNA repair defects harbored germline mutations in either RAD51D or PALB2, with loss-of-heterozygosity in the tumors. The most significant somatic mutations in young patients with diffuse gastric cancer were CDH1, TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. Within the Korean population and within populations of other ethnicities, mutations in CDH1 (42.2%) or TGFBR1 (7.3%) were more frequent in younger patients than in older patients (17.4% and 0.9%, respectively). In contrast, the RHOA mutation (9.2%) was less frequent in younger patients than in older patients (19.1%). CDH1 alterations, but not RHOA mutations, were associated with poor prognosis (hazard ratio, 3.4 (95% CI, 1.5-7.7)), which may be associated with the aggressive clinical course of diffuse-type gastric cancers in young patients. Conclusions: Our largest-ever genomic analysis of diffuse-ty