Telling the story of a gastric cancer through sequencing and functional studies. (a) The primary gastric cancer clone carried CDH1 and TP53 mutations. After it had metastasized to the ovary, the primary gastric cancer acquired an amplification of the FGFR2 locus (black arrow). At this point, the primary tumor was removed by gastrectomy. Some three years later, the patient presented with abdominal masses. Sequencing of the metastatic tumor revealed loss of TGFBR2, but no amplification of FGFR2. Loss of TGFBR2 might have occurred after the clone had spread to the ovary (non-broken blue arrow) or alternatively might have occurred as the metastatic clone transited from the primary to the ovary (broken blue arrow). (b) A schematic representation of the functional validation of candidate oncogenic events. A human gastric cancer cell line harboring mutations in CDH1 and TP53, and an amplification of FGFR2, shows a significant reduction in survival in response to inhibition of the FGF pathway. Murine gastric organoids in which Tgfbr2 is suppressed by knockdown (kd) in the context of cdh1 and Tp53 loss undergo oncogenic transformation in vitro when grown subcutaneously (s.c.) in immunodeficient mice. The resultant tumor shows histology consistent with diffuse gastric cancer and undergoes metastatic spread to the lungs. Abbreviations: CDH1, cadherin-1; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; TGFBR2, TGF-beta receptor type-2; 3D, three-dimensional; TP53, cellular tumor antigen p53.