Somatic Mutations and Deletions of the E-Cadherin Gene Predict Poor Survival of Patients With Gastric Cancer

Abstract

Purpose The prognosis of gastric cancer (GC) is poor, and the molecular pathogenesis players are vastly unknown. Surgery remains the primary option in GC treatment. The aim of this study was to investigate the impact of somatic CDH1 alterations in prognosis and survival of patients with GC. Patients and Methods A series of patients with sporadic and familial GC (diffuse and intestinal; n = 246) were analyzed for somatic CDH1 mutations, promoter hypermethylation, and loss of heterozygosity (LOH) by polymerase chain reaction sequencing. E-cadherin protein expression was determined by immunohistochemistry. Associations between molecular, clinicopathologic, and survival data were analyzed. Results CDH1 somatic alterations were found in approximately 30% of all patients with GC. Both histologic types of sporadic GC displayed LOH in 7.5%, mutations in 1.7%, and hypermethylation in 18.4% of patients. Primary tumors from hereditary diffuse GC, lacking germline CDH1 alterations, showed exclusively CDH1 promoter hypermethylation in 50% of patients. Familial intestinal GC (FIGC) tumors showed LOH in 9.4% and hypermethylation in 17.0%. CDH1 alterations did not associate with a particular pattern of E-cadherin expression. Importantly, the worst patient survival rate among all GCs analyzed was seen in patients with tumors carrying CDH1 structural alterations, preferentially those belonging to FIGC families. Conclusion CDH1 somatic alterations exist in all clinical settings and histotypes of GC and associate with different survival rates. Their screening at GC diagnosis may predict patient prognosis and is likely to improve management of patients with this disease.

Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis

“…Even though multidimensional scaling analysis showed differences between both groups of PCs ( Figure 1B), there were only 38 genes significantly deregulated (3 upregulated and 35 downregulated) in AL PCs (excluding 22 immunoglobulin coding genes, which are physiologically upregulated in normal PCs and mainly reflect differences between clonal vs polyclonal PCs; supplemental Excel File 1). Interestingly, the CDH1 and RCAN tumor-suppressor genes and the GLIPR1 and FAS proapoptotic genes [14][15][16][17][18] were all significantly downregulated in AL; in contrast, IFITM1, which has been associated with more aggressive solid tumors, 19 was overexpressed in clonal PCs. It is worth noting that CD19 and CD81 mRNAs were significantly decreased in AL, confirming the correlation between the iPEP and the GEP of clonal vs normal PCs.…”

Prospective Comprehensive Genomic Profiling of Advanced Gastric Carcinoma Cases Reveals Frequent Clinically Relevant Genomic Alterations and New Routes for Targeted Therapies

“…5) [46]. The differences in alteration frequency may be related to the interrogation of the entire coding sequence of CDH1 in this assay compared with the limited hotspot assessment of exon 7-10 hotspot interrogation in prior series [46,47].…”

“…The differences in alteration frequency may be related to the interrogation of the entire coding sequence of CDH1 in this assay compared with the limited hotspot assessment of exon 7-10 hotspot interrogation in prior series [46,47]. CDH1 somatic mutation has been correlated with the shortest survival in GC, and selection bias may underlie increased CDH1 mutation rates in this series because clinicians may be likely to reach for mutational profiling when options are limited [46]. In reporting these results, caveats for directed germline testing are included.…”

Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin–Deficient Cells

“…1,[4][5][6]. Disrupting E-cadherin's expression or localization has a pronounced impact on a cell's cytoskeletal structure, with changes including misalignment of the microtubule and actin cytoskeletons, defects in cell migration and irregularities in the orientation of the mitotic spindle (7)(8)(9).…”