Intra-tumoral heterogeneity is well recognized to be inherent in biomarker discovery for gastric cancer since the initial reporting of HER2 overexpression. The Cancer Genome Atlas (TCGA) has laid the groundwork for CNAs comprising the mutational landscape of gastric cancer. We aimed to investigate through a genomic single nucleotide polymorphism (SNP) array panel and fluorescence in-situ hybridization (FISH) inter-patient and intra-tumoral spatial heterogeneity of CNAs.
41 gastric adenocarcinoma patient samples treated with upfront surgical resection were retrospectively identified from the City of Hope Biospecimen Repository. CNAs of 891 cancer-related genes at 50-100 Kb resolution and detection of 74 frequent somatic mutations in 9 genes of interest (BRAF, KRAS, EGFR, IDH1, IDH2, PTEN, PIK3CA, NRAS, TP53) were assayed using the Affymetrix OncoScan™ platform. Genome wide coverage outside of the 891 cancer genes were provided at 300 Kb resolution along with genome wide LOH provided at 3-10 Mb resolution. For samples with multiple CNAs detected, FISH was pursued to define down to a single-cell level the spatial distribution of CNAs.
Detectable percentage (%) genomic changes ranged from 0.03 to 73.90%. Lauren intestinal subtype histology correlated strongly with higher % genomic changes compared to diffuse subtype histology (p = 0.0012). Tumors located in the GEJ/cardia/proximal stomach also correlated with higher % genomic changes compared to gastric body/antrum tumors (p = 0.0028). A variety of oncogenic CNAs were observed across patients including high copy gains in EGFR, JAK2, FGFR2, MET, VEGFA, KRAS, NRAS, and PIK3CA. One sample exhibited co-amplification of CD274 and PDCD1LG2 (encoding PD-L1 and PD-L2), in addition to concurrent amplification of ERBB2, JAK2, FGFR2, MET, KRAS, and PIK3CA. FISH images of the spatial distribution of CNAs will be presented.
The inherent spatial intra-tumoral heterogeneity of oncogenic CNAs with de novo disease presentation illustrates the challenges in gastric cancer therapy. Further study will offer insight into strategies on combinatorial and/or sequential targeted and immunotherapeutic approaches.
Clinical trial identification
Legal entity responsible for the study
United States National Institutes of Health - National Cancer Institute
All authors have declared no conflicts of interest.