Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine

Abstract

Background: Cancer is a somatic evolutionary disease, which adapts to environmental cues based on genetic constraints. Using multiregional exome sequencing, we tested the effect of somatic evolution on intratumoral heterogeneity and its putative clinical implications in adenocarcinomas of the stomach and gastroesophageal junction (GC). Methods: The study comprised a prospective discovery cohort of 9 and a validation cohort of 487 GCs. Multiregional whole-exome sequencing was done using 48 tumor samples (range: 3-10 tumor samples/patient) of the discovery cohort.Results: In total, the discovery cohort harbored 16,537 non-synonymous mutations (mutations/sample: median n=159; mutations/patient: median n=369). Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. 53-91% of the non-synonymous mutations were not present in each patient’s sample; 399 genes harbored 2-4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Phylogenetic analyses provided evidence for branched evolution being the most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. Studies on the validation cohort showed that the subclonal loss of SMAD4 is an independent predictor for poor patient outcome.Conclusions: Neutral and non-neutral somatic evolution shape the mutational landscape in GC. It leads to complex spatial intratumoral heterogeneity and may have profound effects on patient management. It provides crucial information for an individualized understanding of clinical prognosis and therapeutic options in GC patients.