Gastric cancer and
esophageal cancer are the second and sixth leading causes of
cancer-related death worldwide. Multiple genomic alterations underlying
gastric cancer and
esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here, we report the results of whole-genome sequencing of 30 samples comprising
tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia
adenocarcinoma (GCA), and four with gastric noncardia
adenocarcinoma. Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of
guanine may be a potential mechanism underlying
cancer mutagenesis. Furthermore, we identified genes with mutations in
gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2,
FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel
cancer-associated genes,
KISS1R, AMH, MNX1, WNK2, and PRKRIR Finally, we identified recurrent chromosome alterations in at least 30% of
tumors in genes, including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the The
Cancer Genome Atlas dataset. Our studies provide new insights into understanding the genomic landscape,
genome instability, and mutation profile underlying
gastric cancer and ESCC development.
Cancer Res; 76(7); 1714-23. ©2016 AACR.