Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.
Graduate School of Biomedical Science, Ajou University School of Medicine, Suwon, Republic of Korea.
Exp Mol Med. 2018 Apr 6;50(4):1-11. doi: 10.1038/s12276-017-0009-6.
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). 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.
弥漫型胃癌（DGC）是一种临床结局具有异质性的 GC 亚型。DGC 的淋巴结转移预示着预后不良，这阻碍了患者的治愈性治疗。然而，DGC 的基因组异质性尚不清楚。为了鉴定与 DGC 淋巴结转移相关的基因组变异，我们对 23 例 DGC 及其配对的非肿瘤组织进行了全外显子测序，并根据是否存在（N3，n=13）或不存在（N0，n=10）区域淋巴结转移比较了突变图谱。总体而言，我们在 DGC 中鉴定了 185 个高频突变基因，包括 CMTM2 中的一个显著新突变，以及 CDH1、RHOA 和 TP53 中的先前已知突变。值得注意的是，CMTM2 的表达可以预测 DGC 的预后结果，但不能预测肠型 GC（IGC），表明 CMTM2 在 DGC 进展中起着关键作用。此外，我们在 DGC 中鉴定出 3p12-pcen 位点的 DNA 拷贝数缺失的反复发生。N0 和 N3 肿瘤的比较表明，N3 肿瘤比 N0 肿瘤表现出更频繁的 DNA 拷贝数异常，包括拷贝中性 LOH 和 CpTpT 三核苷酸的突变（P=0.2×10）。总之，根据淋巴结转移状态，DGC 具有不同的体细胞突变和 DNA 拷贝数谱，这可能有助于描绘 DGC 的病理生物学。
