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 ؊161C3 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. © 2002 Wiley-Liss, Inc. Key words: E-cadherin; mutation; breast cancer; promoter; SNPThe E-cadherin gene (CDH1, OMIM 192090) encodes an adhesion molecule important for establishing cell polarity and maintaining normal tissue morphology and cellular differentiation. 1 E-cadherin was suggested to act as an invasion and metastasis suppressor since its loss in benign tumors could lead to a rapid progression into invasive, metastatic carcinomas. 2 CDH1 was mapped to the chromosome region 16q22.1, 3 which shows frequent allelic imbalance in a variety of tumors and is believed to harbor a tumor-suppressor gene. Mutation analysis of the coding region has been carried out in endometrial and ovarian carcinomas, 4 thyroid, 5 prostate, 6 bladder, 7 colorectal, 8 gastric, 9 breast 10 -14 and colon cancer, 15 but frequent CDH1 mutations were only found in diffuse gastric and infiltrative lobular breast carcinomas. 10,11,16 Although ductal tumors are much more common than lobular breast cancer, CDH1 mutations have been observed in lobular carcinomas at a frequency exceeding 50%, 11 but were not found in ductal tumors in several studies, 10,11,16,17 suggesting a differential role for CDH1 in the development of the 2 malignancies. However, recent studies reported CDH1 alterations in cell lines derived from ductal tumors 18 and in a single case of ductal carcinom...

In order to explore the possible role of E-cadherin in familial cancer, 19 familial breast cancer patients, whose tumours demonstrated loss of heterozygosity (LOH) at the E-cadherin locus, were screened for germline mutations. No pathogenic germline alterations were detected in these individuals. However, a somatic mutation was found (49-2A→C) in one of the tumours. This tumour showed a pattern of both ductal and lobular histology. Another 10 families with cases of breast, gastric and colon cancer were also screened for germline mutations, and no mutations were found. A missense mutation in exon 12 of E-cadherin (1774G→A; Ala592Thr) was previously found in one family with diffuse gastric cancer, and colon and breast cancer. An allelic association study was performed to determine whether the Ala592Thr alteration predisposes to breast cancer. In total, we studied 484 familial breast cancer patients, 614 sporadic breast cancer patients and 497 control individuals. The frequencies of this alteration were similar in these groups. However, a correlation between the Ala592Thr alteration and ductal comedo-type tumour was seen. These results, together with previously reported studies, indicate that germline mutations and, more commonly, somatic mutations in E-cadherin may have an influence on the behaviour of the tumours, rather than predispose to breast cancer.