Genomic Landscape of Poorly Differentiated Gastric Carcinoma: An AACR GENIE® Project

Poorly differentiated gastric carcinoma (PGC) is aggressive, yet subtype-specific genomics are under-characterized. We queried AACR Project GENIE^® (cBioPortal v18.0-public; 12 August 2025) for PGC and analyzed somatic alterations from targeted panels (depth ≥ 100×; variant allele frequency ≥ 5%). Mutation and copy number frequencies were summarized, co-occurrence and exclusivity were tested, and primary versus metastatic tumors were compared using chi-square with Benjamini-Hochberg correction. The cohort included 189 tumors from 188 patients (71% primary; 25% metastatic), with primary and metastatic tumor samples being collected from different patients. Recurrently mutated genes were <i>TP53</i> (48.7%), <i>CDH1</i> (31.2%), <i>ARID1A</i> (21.2%), <i>KMT2C</i> (8.5%), and <i>POLD1</i> (7.4%); additional alterations involved <i>ERBB3</i>, <i>KMT2D</i>, <i>KEL</i>, <i>CDKN2A</i>, and <i>FAT1</i> (≈1-7%). Amplifications in <i>CCNE1</i> (8.2%) and <i>FGFR2</i> (7.6%) were common, alongside gains in <i>MET</i>, <i>MYC</i>, <i>KRAS</i>, and <i>ERBB2</i> and losses in <i>CDKN2A/CDKN2B</i>, <i>CDH1</i>, and <i>PTEN</i>. Significant co-occurrence was observed for <i>POLD1-KMT2D</i> (<i>p</i> < 0.001), <i>POLD1-ARID1A</i> (<i>p</i> < 0.001), and <i>ARID1A-KMT2D</i> (<i>p</i> < 0.001), while <i>TP53</i> was mutually exclusive with <i>ARID1A</i> (<i>p</i> = 0.029) and <i>CDH1</i> (<i>p</i> = 0.041). <i>CDH1</i> (48.9% vs. 29.6%; <i>p</i> = 0.021) and <i>MLH1</i> (8.5% vs. 1.5%; <i>p</i> = 0.040) were enriched in metastases, and <i>CCNE1</i> alterations showed female predominance (<i>p</i> = 2.83 × 10^-4). Several "primary-only" findings likely reflect small denominators and require replication. PGC demonstrates a mutational framework dominated by <i>TP53</i>, <i>CDH1</i>, <i>ARID1A</i>, and recurrent <i>CCNE1</i>/<i>FGFR2</i> amplifications, underscoring dysregulation of cell cycle and chromatin-remodeling pathways as key drivers. Co-occurrence of <i>POLD1</i>, <i>ARID1A</i>, and <i>KMT2D</i> suggests coordinated disruption of DNA repair and epigenetic regulation, whereas mutual exclusivity of <i>TP53</i>, <i>ARID1A</i>, and <i>CDH1</i> indicates distinct tumorigenic routes. Metastatic enrichment of <i>CDH1</i> and <i>MLH1</i> supports their roles in invasion and therapeutic resistance. Together, these findings highlight candidate biomarkers and actionable pathways warranting validation in larger, multi-omic cohorts to refine precision treatment strategies for this aggressive gastric cancer subtype.