CDH1 somatic alterations in Mexican patients with diffuse and mixed sporadic gastric cancer
Andrea Rebeca Bustos-Carpinteyro,
Carla Oliveira,
Abel Sousa,
Patricia Oliveira,
Hugo Pinheiro,
Joana Carvalho,
María Teresa Magaña-Torres,
María Guadalupe Flores-Miramontes,
Adriana Aguilar-Lemarroy,
Luis Felipe Jave-Suárez,
Jorge Peregrina-Sandoval,
José Alfonso Cruz-Ramos,
Josefina Yoaly Sánchez-López
Affiliations
Andrea Rebeca Bustos-Carpinteyro
División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social
Carla Oliveira
Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto
Abel Sousa
Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto
Patricia Oliveira
Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto
Hugo Pinheiro
Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto
Joana Carvalho
Expression Regulation in Cancer, IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto
María Teresa Magaña-Torres
División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social
María Guadalupe Flores-Miramontes
División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social
Adriana Aguilar-Lemarroy
División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social
Luis Felipe Jave-Suárez
División de Inmunología, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social
Jorge Peregrina-Sandoval
Laboratorio de Inmunobiología, Departamento de Biología Celular y Molecular. Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara
José Alfonso Cruz-Ramos
Instituto Jalisciense de Cancerología
Josefina Yoaly Sánchez-López
División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social
Abstract 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.
