mercredi 29 août 2012

Mutated genes in cancer (79) – CDH1


In databases :
Ensembl ( ENSG00000039068
UniProt ( P12830
GeneCards ( CDH1
HGNC ( 1748 or CDH1

Gene locus:


Protein name:

Cadherin 1, type 1, E-cadherin (epithelial)

Protein Size:

882 amino acids; about 97 kDa


One of the most important and ubiquitous types of adhesive interactions required for the maintenance of solid tissues is that mediated by the classic cadherin adhesion molecules. Cadherins are transmembrane Ca2+- dependent homophilic adhesion receptors that are well known to play important roles in cell recognition and cell sorting during development. However, they continue to be expressed at high levels in virtually all solid tissues. There are many members of the classic cadherin family (which is a subset of the larger cadherin superfamily), but E-cadherin in epithelial tissues has been the most studied in the context of stable adhesions. Continued expression and functional activity of E-cadherin are required for cells to remain tightly associated in the epithelium, and in its absence the many other cell adhesion and cell junction proteins expressed in epithelial cells (see below) are not capable of supporting intercellular adhesion. In its capacity to maintain the overall state of adhesion between epithelial cells, E-cadherin is thought to act as an important suppressor of epithelial tumor cell invasiveness and metastasis.

Cancer-related alterations:

Mutations in this gene are correlated with gastric, breast, biliary tract, colorectal, thyroid and ovarian cancer.

Defects in CDH1 are a cause of hereditary familial diffuse gastric cancer (HDGC). Dozens of CDH1 germline mutations have been described in HDGC families. Most are inactivating (frameshift, nonsense, and splice-site), the remainders are “missense”. The mutations are distributed equally throughout the gene.

Somatic mutations in CDH1 were found in about 56% of lobular breast tumors, generally (>90%) in combination with loss of the wild-type allele, while no mutations were found in ductal primary breast carcinomas. Most of these somatic mutations result in premature stop codons as a consequence of insertions, deletions and nonsense mutations leading to the loss of the CDH1 cell-cell adhesion functionality. Other cancer-confined E-cadherin mutations also result in crippled proteins. The distinctive invasive growth pattern, which is typical for lobular breast cancers, is fully compatible with this functional inactivation.

Frequent somatic mutations (50%) in CDH have been identified in sporadic diffuse gastric cancer (DGC). Most mutations are “missense” (exons 8, 9) or exon skipping. In most cases, CDH1 mutations are found in combination with loss of the wild-type allele.

References (open access):

Pathology of hereditary breast cancer. van der Groep P, van der Wall E, van Diest PJ. Cell Oncol (Dordr). 2011 Apr;34(2):71-88.

Hereditary diffuse gastric cancer: prophylactic surgical oncology implications. Lynch HT, Silva E, Wirtzfeld D, Hebbard P, Lynch J, Huntsman DG. Surg Clin North Am. 2008 Aug;88(4):759-78, vi-vii.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, Yorida E, Maines-Bandiera S, Kaurah P, Tung N, Robson ME, Ryan PD, Olopade OI, Domchek SM, Ford J, Isaacs C, Brown P, Balmana J, Razzak AR, Miron P, Coffey K, Terry MB, John EM, Andrulis IL, Knight JA, O'Malley FP, Daly M, Bender P; kConFab, Moore R, Southey MC, Hopper JL, Garber JE, Huntsman DG. J Med Genet. 2011 Jan;48(1):64-8.

E-cadherin polymorphisms and breast cancer susceptibility: a report from the Shanghai Breast Cancer Study. Beeghly-Fadiel A, Lu W, Gao YT, Long J, Deming SL, Cai Q, Zheng Y, Shu XO, Zheng W. Breast Cancer Res Treat. 2010 Jun;121(2):445-52.

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