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 ؊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...

The ductal phenotypic expression of the E-cadherin/catenin complex in tubulolobular carcinoma of the breast: an immunohistochemical and clinicopathologic study

“…E-cadherin is often mutated in lobular neoplasia, resulting in the absence of the extracellular E-cadherin domain and lack of membrane immunostaining for the protein. [5][6][7][8][9][10][11][12][13][14][15] In contrast, mammary carcinomas that are ductal in cell origin almost universally display distinct membrane staining for E-cadherin, although highgrade ductal carcinomas show diminished E-cadherin or rarely, may be E-cadherin negative. 16 Thus, immunohistochemistry for the E-cadherin protein has become a valuable diagnostic tool to differentiate ductal from lobular carcinomas.…”

BACH1 517C→T transition impairs protein translocation to nucleus: A role in breast cancer susceptibility?

“…Controls were randomly selected female blood donors from the same attraction region. 15 We found 1 unaffected and 3 affected cases with the 517T/C genotype, indicating the presence of this polymorphism in a different population and a similar allelic frequency in both groups (0.3% vs. 0.5%). The combined data indicated the presence of the 517T allele in 6 of 765 (0.39%) cases and 3 of 406 (0.37%) controls in Caucasians.…”

“…Five micrograms of the wild-type BACH1, BACH1-517T and BACH1-⌬NLS1 plasmid constructs were used for transfections using a calcium phosphate method as described previously. 15 The pEGFP-C2 plasmid served as a control. Samples were fixed at 12, 24, 36 and 48 hr after transfection and mounted onto a glass microscope slide using FluorSave reagent (CalBiochem, San Diego, CA).…”

“…The ascertainment of both controls and cases was as described. 15 Briefly, blood samples from 151 patients were obtained from consecutive and unselected cases of breast cancer, while DNA from infiltrative lobular breast cancer carriers was extracted from the paraffin-embedded blocks surrounding cancerous tissue that were selected from a large cohort of breast cancer patients diagnosed from 1992-2000. Controls were randomly selected female blood donors from the same attraction region.…”

Effect of genetics, epigenetics and variations in the transcriptional expression of cadherin–E in breast cancer susceptibility

“…En algunos estudios se ha analizado la relación de otro polimorfismo en esta región del CDH1, la variante -160A, con el riesgo de desarrollar cáncer de mama y no se ha encontrado asociación (21,22), mientras que en algunos otros estudios, se encontró un aumento significativo del riesgo de desarrollar este cáncer (10,23). Los resultados concernientes al efecto de las variables en la región promotora del CDH1 y su asociación con el cáncer de mama no fueron suficientemente claros, por lo que es necesario determinar el efecto real de estas mutaciones en el funcionamiento de la proteína.…”