CDH1 mutations are present in both ductal and lobular breast cancer, but promoter allelic variants show no detectable breast cancer risk

• Published in: International journal of cancer Vol. 98; no. 2; pp. 199 - 204
• Main Authors: Lei, Haixin, Sjöberg‐Margolin, Sara, Salahshor, Sima, Werelius, Barbro, Jandáková, Eva, Hemminki, Kari, Lindblom, Annika, Vořechovský, Igor
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 10-03-2002; Wiley-Liss
• Subjects: Adenine Nucleotides - genetics; Alleles; Biological and medical sciences; breast cancer; Breast Neoplasms - genetics; Cadherins - genetics; Carcinoma, Ductal, Breast - genetics; Carcinoma, Lobular - genetics; E‐cadherin; Female; Gene Frequency; Genes, Reporter; Genetic Predisposition to Disease; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Medicin och hälsovetenskap; Mutation; Polymorphism, Genetic; promoter; Promoter Regions, Genetic; SNP; Transcriptional Activation; Tumor Cells, Cultured; Tumors; Sweden; Europe; Human; Ductal carcinoma; Genetic variability; Transcription promoter; Genotype; Lobular carcinoma; Malignant tumor; Case control study; Epidemiology; Mammary gland diseases; Gene; Risk factor; Genetics; Mammary gland; Mutation; E Cadherin; Public health; Polymorphism
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.10176

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. © 2001 Wiley‐Liss, Inc.