Hereditary diffuse gastric cancer and E-cadherin: Description of the first germline mutation in an Italian family

doi:10.1016/j.ejso.2006.10.028

European Journal of Surgical Oncology (EJSO)

Volume 33, Issue 4, May 2007, Pages 448-451

https://doi.org/10.1016/j.ejso.2006.10.028 Get rights and content

Abstract

Aims

Germline mutation of the E-cadherin gene (CDH1) accounts for the Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Fourteen pedigrees with Diffuse Gastric Cancer that fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria were selected and screened for CDH1 germline mutations.

Methods

The entire coding region of the CDH1 gene and all intron–exon boundaries were analyzed by direct sequencing in the 14 families fulfilling the IGCLC criteria. E-cadherin immunohistochemical expression was evaluated on tumour as well as normal formalin-fixed paraffin embedded tissues.

Results

A novel germline missense mutation was found. It was a single C → T substitution in exon 8, resulting in a transition of CCG → CTG (C1118T; Pro373Leu) demonstrated in the proband and her brother. At immunohistochemical analysis, the staining intensity was reduced and considered weakly positive (15%).

Conclusions

The first CDH1 germline mutation of an Italian family is herein reported. The present missense mutation has never been described so far.

Introduction

Hereditary Diffuse Gastric Cancer (HDGC) is an autosomal dominant familial syndrome associated with the diffuse histotype and caused by germline mutations in the E-cadherin gene (CDH1).¹ CDH1 gene maps to chromosome 16q22.1 and comprises 16 exons encoding for E-cadherin protein.² E-cadherin is a transmembrane glycoprotein responsible for cell-to-cell adhesion and its deregulation is correlated with infiltrative and metastatic ability of the tumour.3, 4 Originally, CDH1 germline mutation was described in three Maori families by Guilford and colleagues in 1998⁵; subsequently, additional germline mutations have been identified in families from several countries.⁶ No patients with CDH1 germline mutations have been described in Italy so far.⁷

This study reports the first novel CDH1 germline missense mutation identified in Italian families.

Section snippets

Methods

Familial history was retrospectively investigated according to the International Gastric Cancer Linkage Consortium (IGCLC) criteria in order to search for families with potential Hereditary Diffuse Gastric Cancer (HDGC) in 238 patients affected by primary gastric cancer and operated on at the Division of General Surgery and Surgical Oncology, University of Siena, Italy, between January 1988 and December 2004. The adopted criteria were the following: two or more documented cases of diffuse

Results

Fourteen families fulfilled the IGCLC clinical criteria. Eight families (57.1%) had two first-degree members with histologically confirmed diffuse gastric cancer of which at least one diagnosed before the age of 50 and 6 (42.9%) had three first-degree relatives diagnosed with diffuse gastric cancer independent of the age of onset.

The 14 HDGC patients were screened for CDH1 germline mutations and a novel missense mutation was identified in one family. It was a single C → T substitution in exon 8,

Discussion

In 1998 Guilford and colleagues described the first germline mutation of E-cadherin gene in three Maori families with predisposition to autosomal dominant diffuse gastric cancer.⁵ According to the most recent review, 58 CDH1 germline mutations have been described, of which 19 (33%) are of the missense type.¹¹

The CDH1 germline mutation herein reported is a missense mutation never described so far; this results as a single C → T substitution in exon 8, causing a transition of CCG → CTG (C1118T;

Acknowledgements

This work has been supported by grant PAR 2004, University of Siena, and by grant MIUR 2005 to Unit of Surgical Oncology, University of Siena, Italy.

Conflict of interest: None declared.

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Hereditary diffuse gastric cancer and E-cadherin: Description of the first germline mutation in an Italian family

Abstract

Aims

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

Curr Opin Cell Biol

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria

J Med Genet

E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers

EMBO J

Cadherin cell adhesion receptors as a morphogenetic regulator

Science

E-cadherin germline mutations in familial gastric cancer

Nature

Familial gastric cancer: overview and guidelines for management

J Med Genet

Screening E-cadherin germline mutations in Italian patients with familial diffuse gastric cancer: an analysis in the District of Urbino, Region Marche, Central Italy

Tumori