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ABSTRACT Background: Early-onset diffuse gastric cancer (EODGC) occurs at or before 50 years of age. Pathogenic mutations and germline deletions in the CDH1 gene (E-cadherin) are well-documented genetic factors associated with the causes of EODGC. Objective: The objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population. Methods: We studied seven EODGC patients from a biomedical research center in western Mexico. Variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. The DeepSEA and SNPClinic v.1.0 software and the Ensembl (1000 Genomes Project, 1kGP) and ClinVar databases were used to predict functional single-nucleotide polymorphisms (SNPs). The genetic admixture of the Mexican patients was corroborated by 22 short tandem repeat loci genotyping and structure analysis. Results: We found 12 germline CDH1 variants in all EODGC patients, and all of them are considered as polymorphisms: rs34561447, rs5030625, rs16260, rs1330727101, rs28372783, rs942269593, rs3743674, rs1801552, rs34939176, rs33964119, rs3556654, and rs1801026. The prediction of regulatory SNPs in the promoter suggests a role for a retrovirus in EODGC that induces the transcription of interferon-related genes through toll-like receptor-interferon response factor 3 signaling, as three SNPs in the CDH1 promoter alter three binding sites for this transcription factor. In addition, SNPs rs28372783 and rs1801026 could alter upstream stimulatory factors 1 (USF1)/USF2-mediated telomerase-dependent lymphocyte activation in EODGC. Other interesting result is a CTCF-dependent shorter CDH1 isoform lacking exon 14, probably due to exon-skipping mediated by rs33964119. Conclusions: Classical pathogenic germline mutations in the CDH1 gene were not found in these 7 EODGC patients. However, the in silico approaches revealed the possible involvement of a retrovirus and a shorter E-cadherin isoform in EODGC. Nevertheless, further in vitro and in vivo assays are needed to confirm these predictions.
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Objective To explore the significance of gene promoter methylation of CDH1 in breast invasive ductal carcinoma.Methods The gene promoter methylation of CDH1 and E-cadherin expression status in breast cancer tissues,adjacent tissues and normal breast tissues were detected by using methylation specific polymerase chain reaction (PCR) and immunohistochemistry (SP) method.The clinicopathological data (genetic background,age,tumor size,axillary lymph node metastasis,tumor cells grading,clinical staging and molecular subtype) were collected,and analysed the clinical significance of gene promoter methylation of CDH1 in breast cancer.Results Among the 250 patients with breast cancer,113 cases were found gene promoter methylation of CDH1,and the methylation rate was 45.20％.Compared with patients with unmethylated CDH1 gene promoter,the E-cadherin protein expression was reduced in patients with methylated CDH1 gene promoter,there was statistically significant difference (x2 =21.360,P＜0.01).The univariate analysis showed that statistically significant differences were found in axillary lymph node metastasis (x2=19.086,P＜0.01),histological grading of tumor (x2 =8.487,P=0.014),CerbB-2 expression (x2=9.475,P=0.002) and molecular typing (x2 =25.482,P＜0.01) between patients with methylated and unmethylated CDH1 gene promoter.The COX regression analysis showed that there was significant difference in 5-year survival rate between patients with methylated and unmethylated CDH1 gene promoter(P＜0.01).Conclusion Methylation of CDH1 gene promoter causes decreasedexpression of mRNA,and is associated with axillary lymph node metastasis in breast cancer,which suggests that methylation of CDH1 gene promoter plays a certain role in breast cancer progression.
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Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited disease,and may be related to the mutation of CDH1 or CTNNA1 genes.Microscopically,signet-ring cell carcinoma is suggested frequently in endoscopic biopsy or gastrectomy specimens.Some patients may have concomitant extra-stomach tumor (frequently breast cancer in females).Detection of CDH1 gene mutation should be performed in high-risk individuals,and diagnosis and treatment should be carried out by a multidisciplinary team.Prophylactic gastrectomy is recommended for those with pathogenic CDH1 mutation.Endoscopic surveillance is an option for those with CDH1 mutation of undetermined significance and those without germline CDH1 mutation.This review discussed the concept,genetic characteristics,clinicopathological features and genetic screening of HDGC for providing a reference for clinicians.