Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management

Eur J Surg Oncol. 2007 Nov;33(9):1061-7. doi: 10.1016/j.ejso.2007.03.001. Epub 2007 Apr 16.


Aim: Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by E-cadherin germline mutations. One-third of these mutations are of the missense type, representing a burden in genetic counselling. A new germline missense mutation (P373L) was recently identified in a HDGC Italian family. The present work aimed at addressing the disease-causative nature of the P373L mutant.

Methods: Assessment of the P373L mutation effect was based on cell aggregation and invasion assays. LOH analysis at the E-cadherin locus, search for somatic E-cadherin mutations and for promoter hypermethylation were performed to identify the mechanism of inactivation of the E-cadherin wild-type allele in the tumour.

Results: In vitro the P373L germline mutation impaired the E-cadherin functions. E-cadherin promoter hypermethylation was observed in the tumour of the P373L mutation carrier.

Conclusion: We conclude that the combination of clinical, in vitro and molecular genetic data is helpful for establishing an accurate analysis of HDGC-associated CDH1 germline missense mutations and subsequently for appropriate clinical management of asymptomatic mutation carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Cadherins / genetics*
  • Carrier State / physiopathology
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • DNA Methylation
  • Germ-Line Mutation*
  • Humans
  • Mutation, Missense*
  • Neoplasm Invasiveness / genetics
  • Polymorphism, Single Nucleotide
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology


  • Cadherins