Abstract

Diffuse-type gastric cancer (DGC) is a GC subtype with heterogeneous clinical outcomes. Lymph node metastasis of DGC heralds a dismal progression, which hampers the curative treatment of patients. However, the genomic heterogeneity of DGC remains unknown. To identify genomic variations associated with lymph node metastasis in DGC, we performed whole exome sequencing on 23 cases of DGC and paired non-tumor tissues and compared the mutation profiles according to the presence (N3, n = 13) or absence (N0, n = 10) of regional lymph node metastasis. Overall, we identified 185 recurrently mutated genes in DGC, which included a significant novel mutation at CMTM2, as well as previously known mutations at CDH1, RHOA, and TP53. Noticeably, CMTM2 expression could predict the prognostic outcomes of DGC but not intestinal-type GC (IGC), indicating pivotal roles of CMTM2 in DGC progression. In addition, we identified a recurrent loss of heterozygosity (LOH) of DNA copy numbers at the 3p12-pcen locus in DGC. A comparison of N0 and N3 tumors showed that N3 tumors exhibited more frequent DNA copy number aberrations, including copy-neutral LOH and mutations of CpTpT trinucleotides, than N0 tumors (P = 0.2 × 10⁻³). In conclusion, DGCs have distinct profiles of somatic mutations and DNA copy numbers according to the status of lymph node metastasis, and this might be helpful in delineating the pathobiology of DGC.