title: CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk.
abstract: Mutations and diminished expression of the E-cadherin gene (CDH1) have been identified in a number of epithelial malignancies. Although somatic CDH1 mutations were detected in lobular breast cancer with a frequency ranging from 10-56%, CDH1 alterations in more frequent ductal tumors appear to be rare. Here we have analyzed the coding region of CDH1 for mutations using denaturing high performance liquid chromatography and found 4 mutations in 83 ductal carcinomas (5%) and 3 mutations in 25 lobular carcinomas (12%). The germline of 13 patients with familial lobular tumors was also analyzed for mutations, but none were detected. In a case-control study, we also tested whether a variant adenine allele in the promoter polymorphism -161C-->A with a putative influence on the transcriptional activity of CDH1 in vitro confers any detectable risk of breast cancer. No significant difference in the allelic frequency between patients with breast cancer (326/1,152, 28.3%) and controls (190/696, 27.3%, p > 0.05; relative risk 1.05, 95% confidence interval 0.85-1.30) was found. A novel promoter polymorphism was identified at position -152, but the frequency of the variant cytosine allele was also similar in patients with breast cancer and controls (0.71% vs. 0.21%, p = 0.23). Transient transfection experiments using reporter constructs containing the nucleotide substitutions -161C/-152C and -161A/-152T showed only a slight decrease in the transcription activity compared to the wild-type construct. These results do not support CDH1 as a prominent low-penetrance cancer susceptibility gene, but indicate that CDH1 mutations contribute to the progression of both lobular and ductal tumors.
authors.affiliation: Karolinska Institute, Department of Biosciences at NOVUM, Huddinge, Sweden.
authors.forename: Haixin
authors.initials: H
authors.lastname: Lei
authors.forename: Sara
authors.initials: S
authors.lastname: Sjöberg-Margolin
authors.forename: Sima
authors.initials: S
authors.lastname: Salahshor
authors.forename: Barbro
authors.initials: B
authors.lastname: Werelius
authors.forename: Eva
authors.initials: E
authors.lastname: Jandáková
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Igor
authors.initials: I
authors.lastname: Vorechovský
mesh_terms: D000227:Adenine Nucleotides / Q000235:genetics; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D018275:Carcinoma, Lobular / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D000227:Adenine Nucleotides; D015820:Cadherins