Near-Comprehensive Resequencing of Cancer-Associated Genes in Surgically Resected Metastatic Liver Tumors of Gastric Cancer

Abstract

Liver metastasis is a major cause of death in patients with gastric cancer. The molecular alterations in clinically resected liver metastases of gastric cancer were evaluated to identify candidate biomarkers and therapeutic targets. Seventy-four patients, including 37 with liver metastasis who underwent gastrectomy and hepatectomy for gastric cancer and 37 without liver metastasis who underwent gastrectomy for gastric cancer, were studied. Next-generation resequencing was performed for 412 cancer-associated genes in metastatic and/or primary tumors from 30 patients and somatic mutations in TP53, LRP1B, PIK3CA, ADAMTS20, PAX7, FN1, FOXO3, WRN, PTEN, ETV4, and RNF213 were found in metastatic tumors. TP53 mutations were studied by Sanger sequencing in the remaining patients; the number of patients with TP53 mutations in metastatic tumors was significantly higher among those with liver metastasis (86.5%, 32/37) versus those without liver metastasis (40.5%; 15/37; P<0.0001). TP53 mutations in metastatic liver tumors and corresponding primary tumors were identical in 96.9% (31/32), including some patients with heterogeneous primary tumor components. Immunohistochemical analyses showed aberrant p53 expression in tumors with TP53 mutations. In silico functional evaluations indicated functional loss of missense-mutated TP53. Thus, the p53 pathway may facilitate the development of biomarkers and therapeutic approaches to treat gastric cancer metastases to the liver.