Exome analysis of over 5000 esophagogastric cancers.

4073 Background: Esophagogastric cancers (EGCs) encompass a heterogenous group of cancers. The genomic drivers that overlap or differentiate among each cancer type are not well studied, despite the availability of therapies that target specific genetic alterations in driver genes. Methods: Genomic data from Natera's Real-World Database (N = 5,872) was analyzed to investigate genomic patterns in EGC patients (09/2019-11/2024) receiving standard-of-care treatment . This exploratory analysis was conducted on tumor tissue data available from whole-exome sequencing, generated as part of SignateraTM testing.Microsatellite instability (MSI) status was determined using the MSIsensor and 96-trinucleotide contexts and was correlated with COSMIC SBS signatures (v3.3). Prevalence analysis included only non-synonymous mutations, with ranking adjusted for gene length. Results: Patients included 4050 men and 1822 women, with median age 65.3 years, and stage distribution as follows: I: 7.9%, II:14.7%, III: 32.9%, IV: 32.2%, and 12.3% unknown. Gastric cancer (GC) was most common (48.1%), followed by esophageal (EC, 45.9%) and gastroesophageal junction (GEJ, 7.2%). MSI-high cases (7.7% prevalence overall, 2.2% in squamous EC, 5.2% in EC adenocarcinoma, 6.1% in GEJ, 10.9% in GC) had a distinct mutational landscape with frequent missense deletions. The most common signatures were clock-like (SBS1, SBS5), MMR-deficiency-related (SBS6, SBS15), and Thiopurine-chemotherapy-related (SBS87). PIK3CA mutations were found in 7.9% of cases, with the most common being E545 (2.6%), H1047 (1.1%), and E542 (1.0%). Notably, PIK3CA exon 9/20 mutations displayed a trend of higher prevalence in ctDNA-positive cases. Conclusions: These data provide insights into the mutational landscape of EGC and enhance our understanding of differences between histological subtypes. Future studies will continue to explore the associations between genomic subtypes, treatment patterns, and clinical outcomes. Top mutated genes and variants in esophagogastric cancers. Group N Genes Variants EGC, all 5872 TP53 (49.8%) ARID1A (16.1%) ACVR2A K437X (5.5%) RPL22 K15X (5.3%) RNF43 G659X (4.0%) EGC, MSS 5411 TP53 (47.9%) ARID1A (11.9%) G2E3 T361fs (3.1%) TP53 R175H (2.7%) LRRIQ3 Q245fs (2.3%) EGC, MSI-high 422 ARID1A (71.7%) KMT2D (68.7%) RPL22 (60.3%) ACVR2A K437X (58.6%) RPL22 K15X (56.6%) RNF43 G659X (44.1%) GEJ, MSS 448 TP53 (50.5%) CSMD1 (13.4%) PCLO (12.0%) TMBIM4 Y174fs (3.2%) TP53 R273C (3.2%) TP53 R175H (3.2%) GC, MSS 2487 TP53 (33.5%) CDH1 (14.4%) ARID1A (13.8%) G2E3 T361fs (3.1%) PIK3CA E545K (2.3%) LRRIQ3 Q245fs (2.2%) EC Adenocarcinoma, MSS 1599 TP53 (33.5%) CDKN2A (13.5%) ARID1A (12.6%) TP53 R175H (4.0%) TP53 R248Q (3.4%) G2E3 T361fs (3.1%) EC Squamous carcinoma, MSS 348 TP53 (61.8%) NOTCH1 (17.2%) PIK3CA E545K (3.9%) TMBIM4 Y174fs (3.4%) TP53 Y220