Lymph node metastasis evolution drives cancer immune evasion and drug resistance

Gastro-esophageal adenocarcinomas (GEAs) are aggressive cancers and multiple trials of targeted therapies recently failed to improve survival in these tumors. Intratumor heterogeneity (ITH) is suspected to contribute to poor outcomes. Here we investigate the degree of ITH in multiple primary and metastatic regions of gastric adenocarcinoma tumours. ITH increased significantly with lymph node metastasis formation and subclonal aberrations activating the Mitogen Activated Protein Kinase (MAPK)-pathway were significantly enriched in nodal metastases. This shows that selection pressures in the lymph node ecosystem differ from those in the primary tumor, leading to evolutionary convergence of distinct tumors when they spread to lymph nodes. We used Oncoscan arrays to analyse multiple regions from nine GEA primary tumors and associated lymph node metastases. Somatic mutation and DNA copy number analysis identified ITH in all tumors. Eight chromosomally instable GEAs predominantly evolved through DNA copy number aberrations whereas a microsatellite instable tumor exclusively evolved through point mutations and showed evidence for parallel evolution. We used Oncoscan arrays to analyse multiple regions from nine GEA primary tumors and associated lymph node metastases. Somatic mutation and DNA copy number analysis identified ITH in all tumors. Eight chromosomally instable GEAs predominantly evolved through DNA copy number aberrations whereas a microsatellite instable tumor exclusively evolved through point mutations and showed evidence for parallel evolution. We used Oncoscan arrays to analyse multiple regions from nine GEA primary tumors and associated lymph node metastases. Somatic mutation and DNA copy number analysis identified ITH in all tumors. Eight chromosomally instable GEAs predominantly evolved through DNA copy number aberrations whereas a microsatellite instable tumor exclusively evolved through point mutations and showed evidence for parallel evolution.