E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer

Abstract

Aim

CDH1 germline alterations occur in about 40% of hereditary diffuse gastric cancer (HDGC) families. CDH1 germline mutations are also documented in few early onset diffuse gastric cancer patients (EODGC) without family history, but the real frequency in this setting in unknown. In these patients, the advanced stage at the time of diagnosis remains a clinical burden due to the poor long term survival.

Methods

The entire coding region and exon flanking sequences of the CDH1 gene was analysed by direct sequencing in 21 EODGC patients aged ⩽50 years. The potential deleterious nature for a new CDH1 missense variant was assessed by cell–cell aggregation and invasion assays. Somatic CDH1 mutation, loss of heterozigosity (LOH) and promoter hypermethylation was explored in the tumour from one CDH1 germline mutation carrier.

Results

Two novel CDH1 germline variants were identified in 21 EODGC cases, c.670C>T and –63C>A. Functional analysis of the c.670C>T missense variant classified this mutation as non-pathogenic. The analysis of CDH1 somatic second hits failed to demonstrate E-cadherin structural and epigenetic alterations in the tumour sample.

Conclusion

Data from the present work and a systematic review of the literature revealed that CDH1 germline mutations occurred in 7.2% of EOGC patients invariably with diffuse of mixed histology. From these, proved CDH1 mutation pathogenicity has been assigned only to 2.3% of the cases who were recurrently diagnosed before 35 years old. Germline CDH1 mutation remain the only germline genetic defect described in this type of patients and CDH1 mutation screening should be recommended for patients with these characteristics.

Introduction

Gastric cancer (GC) represents the second most frequent cause of cancer related death and the 4th most common malignancy worldwide.1, 2, 3, 4

Several genetic, epigenetic and environmental factors interact simultaneously in the early steps of gastric carcinogenesis. Amongst these, human genetic polymorphisms of some inflammatory-related genes are thought to be responsible for an increased risk of GC.5, 6 Other factors such as tobacco consumption, dietary habits and Helicobacter pylori infection7, 8, 9 have been demonstrated to be involved in the multifactor process of gastric carcinogenesis.

Over the last years, the incidence of GC, especially the intestinal histotype, has been decreasing in older patients, remaining otherwise stable in young patients and in cases with diffuse histotype.¹⁰ This would suggest that the aetiology of GC in young people may be different compared to older subjects. In the older population, the association of different environmental factors and epigenetic changes frequently relates to GC development. In young patients, the role of genetics is presumably greater, environmental carcinogens playing a less significant role.¹¹

EOGC is defined as any GC presenting at the age of 45 or earlier and represents approximately 10% of all patients with stomach cancer with reported frequencies varying between 2.7% and 15% according to different populations studied.12, 15, 16, 17 GC patients younger than 40–45 years old are believed to develop GCs involving molecular pathways different from those of sporadic carcinomas that occur later in life.12, 13, 14 GC that occurs in patients younger than 30 years is very rare (1.1–1.6%) and most of EOGCs are diagnosed in patients older than 35.18, 19 GC’s diagnosed before 20 years of age are exceptional and current literature is limited to a small number of cases.16, 20, 21

EOGC may occur in sporadic or hereditary forms. Germline inactivating mutations and deletions of the E-cadherin gene (CDH1) are a well-documented genetic factor associated with diffuse histotype of EOGC (EODGC) or with the HDGC syndrome.22, 23, 24 HDGC is an autosomal dominant cancer disease and represents 1% of all GCs and notably, germline alterations of the CDH1 gene are detected in about 40% of families that fulfil the clinical criteria for the HDGC syndrome.24, 25, 26

Germline mutations of CDH1 gene have also been documented in diffuse EOGC with and without inherited predisposition for the HDGC syndrome.22, 23, 27 Considering the apparently sporadic cases, about 6% of diffuse EOGCs are described to carry a constitutional potentially deleterious sequence variant of E-cadherin gene.²⁸

In this study, we screened for the presence of CDH1 germline alterations in 21 EOGC patients with diffuse histotype and without family history of GC. Additionally, we revised the clinico-pathologic and molecular features presented by EOGC described in the literature, namely in those patients carrying CDH1 germline alterations.