Identification of genomic aberrations associated with lymph node metastasis in diffuse-type gastric cancer

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.

Multiplex profiling of peritoneal metastases from gastric adenocarcinoma identified novel targets and molecular subtypes that predict treatment response

“…These two subtypes are rarely represented in patients with advanced GAC. Recurrent somatic alterations in TP53, CDH1 and RHOA have been reported in diffuse-type primary GACs 10–14. Most recently, Choi et al demonstrated that CMTM2 plays a role in diffuse-type GAC and lymph node metastases in a small patient cohort 11.…”

“…Recurrent somatic alterations in TP53, CDH1 and RHOA have been reported in diffuse-type primary GACs 10–14. Most recently, Choi et al demonstrated that CMTM2 plays a role in diffuse-type GAC and lymph node metastases in a small patient cohort 11. Kurashige et al identified DDR2 as a potential driver gene and novel therapeutic target for those forming PC, by analysing four metastatic cell lines 15.…”

Long noncoding RNA LINC01391 restrained gastric cancer aerobic glycolysis and tumorigenesis via targeting miR-12116/CMTM2 axis

“…As a transcription factor, CMTM2 expression was downmodulated in HCC tissues, and low CMTM2 expression was associated with the poor prognosis of HCC patients, suggesting a potential tumor suppressor role of CMTM2 in HCC progression [24]. Moreover, a significant novel mutation at CMTM2 was correlated with lymph node metastasis in diffuse-type gastric cancer (DGC), and CMTM2 overexpression significantly restrained cell proliferation in GC cells [25]. Based on these studies and our above results, we hypothesized that LINC01391 may be partially required for CMTM2 to exert its anti-oncogenic effect in GC.…”

Unveiling the Genomic Landscape of Gastric Cancer Diagnosis, a Snapshot

“…The association among HER2, MET and FOXP3 expression highlights the role of tissue differentiation in gastric adenocarcinoma [43] and identification of genomic aberrations associated with lymph node metastasis in diffuse-type GC provides profiles of somatic mutations and DNA copy numbers [44]. Likewise, intraperitoneal TAMs are expected to be a promising target in the treatment of peritoneal dissemination in gastric cancer [45].…”