CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer.

BACKGROUND: Diffuse gastric cancer (DGC) is associated with the reduction or absence of the expression of the cell adhesion protein E-cadherin (encoded by the CDH1 gene). Molecular characteristics are less well described for mixed gastric cancer (MGC). The main somatic alterations that have been described in the CDH1 gene are mutations, loss of heterozygosity (LOH) and promoter methylation. The aim was to analyze CDH1 somatic alterations in Mexican patients with diffuse and mixed gastric cancer. METHODS: We searched for mutations in the CDH1 gene in tumor DNA from DGC (n = 13) and MGC (n = 7) patients by next generation sequencing (NGS). Validation of findings was performed using Sanger sequencing. LOH was analyzed using dinucleotide repeat markers surrounding the CDH1 gene, and methylation was investigated by DNA bisulfite conversion and sequencing. E-cadherin protein deficiency was analyzed by immunohistochemistry. RESULTS: Seventeen point variants were identified by NGS, 13 of them were validated by Sanger sequencing. Only 1/13 had not been previously reported (c.-137C > A), and 12/13 were already reported as polymorphisms. Two DGC cases presented LOH at the locus 16q22.1 (13.3%). CDH1 promoter methylation was positive in (7/11) 63.6% and (4/6) 66.6% of the cases with DGC and MGC, respectively. E-cadherin protein deficiency was observed in 58.3% of DGC cases while 100% in MGC cases. CONCLUSIONS: While no pathogenic somatic mutations were found that could explain the diffuse histology of gastric cancer in DGC and MGC, methylation was the most common somatic inactivation event of the CDH1 gene, and LOH was rare. The previously unreported c.-137C > A variant modify the CDH1 gene expression since it alters the binding sites for transcription factors.

[Risk factors associated to diffuse gastric cancer and intestinal histological patterns in an adult population from Western Mexico]. / Factores de riesgo asociados a adenocarcinoma gástrico de patrones histológicos de tipo intestinal y difuso en población adulta del occidente de México.

INTRODUCTION: Gastric cancer (GC) is the third leading cause of cancer death worldwide, and is divided histologically in diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC). Multiple risk factors have been associated with GC in different populations. The objective was to analyze the risk factors associated to DGC and IGC in a population from the western region of Mexico. MATERIAL AND METHODS: The DGC (n = 27) and IGC (n = 26) cases, each matched by age and sex with a control group, were analyzed. Diet and lifestyle data were obtained by a questionnaire. Statistical analysis was performed with the software SPSSv18. The association of risk was calculated in odds ratio (OR); a value of p < 0.05 was considered significant. RESULTS: In the DGC group, the factors with significant OR values were: consumption of pork OR: 3.4 (1.11-10.4; p =0.032), smoking OR: 4.7 (1.5-15.0; p =0.007), green vegetables OR: 0.16 (0.03-0.83; p =0.029) and fruit OR: 0.28 (0.08-0.88; p =0.029). In the IGC group, the consumption of canned sardines was a significant risk factor OR: 4.07 (1.25-13.24; p =0.019). CONCLUSIONS: This work is the first to analyze the risk factors associated with GC in a population from western Mexico.

Los receptores epidérmicos humanos en el cáncer gástrico: alteraciones moleculares y su papel como diana terapéutica.

Gastric cancer (GC) is the third leading cause of cancer death worldwide; both environmental and genetic factors are involved in the etiology of this neoplasia. The human epidermal receptor (HER) pathway is essential for proliferation and differentiation of normal cells; but it is also implicated in the growth of cancer cells. In this work we investigate the molecular alterations in genes that encodes for HER receptors reported in GC, as well the role as therapeutic targets. We reviewed the literature reported to date regarding overexpression of HER-receptors, amplification and somatic mutations in ERBB genes occurred in gastric tumors, as well as the anti-HER therapies tested for treatment of GC. In GC, the overexpression of HER family is reported in a range of 12-87% of cases; up to 67% of cases with amplification, and 90 somatic mutations in ERBB genes. The only drug anti-HER approved for using combined with chemotherapy, in treatment of patients with advanced GC is trastuzumab; however, other targeted therapies are being investigated. The role of the HER family as a therapeutic target has not shown significant improvements in recent years; hence, further studies are required to find better options for treatment of GC.

Analysis of the polymorphisms EGFR-r521K and ERBB2-I655V in Mexican patients with gastric cancer and premalignant gastric lesions.

The proto-oncogenes epidermal growth factor receptor (EGFR) and erythroblastic leukemia viral oncogene homolog 2 (ERBB2), are involved in the development of diverse malignant tumors, including gastric cancer. We analyzed the association of SNPs EGFR-R521K and ERBB2-I655V with gastric cancer and premalignant gastric lesions in Mexican patients. Through restriction fragment length polymorphisms, we analyze both SNPs in the DNA from 155 patients with gastric cancer and premalignant gastric lesions, 121 controls, and 103 people from the Mexican general population. The frequencies of both SNPs did not differ significantly between any of the groups (chi2 p = NS); Odds ratio analysis showed that the alleles EGFR-521K and ERBB2-655V were not related to gastric cancer or premalignant gastric lesions in the Mexican population. Our data suggest that the EGFR-R521K and ERBB2-I655V polymorphisms are not suitable as markers for identifying individuals with a higher risk for developing gastric cancer in our population.