E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer
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.
Section snippets
Patients and sample preparation
From 1993 to 2005, 26 patients with diagnosed sporadic diffuse GC and age at onset ⩽50 years were admitted at the Department of Human Pathology and Oncology, Section of Surgical Oncology, of the University of Siena, Italy; 5 patients were excluded since they not have stored biological material. Twenty-one GC patients younger than 50 years old (n = 11 younger than 45 and n = 10 older than 45) were therefore included in the study. Family histories were obtained with informed consent and pedigree
CDH1 genetic screening revealed two novel germline potentially deleterious sequence variants
Table 1 encompasses the main clinico-pathologic features of the 21 gastric carcinoma patients considered in this study.
We performed CDH1 germline mutation screening in our series of 21 EOGC patients and 2/21 (9.5%) were found to display previously unidentified germline CDH1 sequence variants. None of the remaining 19 patients displayed other potentially deleterious sequence variants of CDH1.
The first patient, a 46 years old female with diffuse GC without further history of gastric cancer in the
CDH1 germline sequence variants and EOGC
CDH1 encodes the E-cadherin tumour suppressor protein that acts as a trans-membrane calcium dependent glycoprotein and plays an essential role in the intercellular adhesion between epithelial cells.34
Decreased E-cadherin expression is often found in several epithelial neoplasias during tumour progression and is correlated with a higher infiltrative and metastatic ability of the tumour35 due to loss of cell adhesion and increased cell motility.36
Typically, inactivating E-cadherin alterations are
Conclusion
Approximately 2.3% of EOGC cases, without family history of GC, display deleterious CDH1 germline alterations. These tumours invariably present partial (mixed) or complete diffuse histology and occur in patients younger than 35 years old. Germline CDH1 mutation screening is now recommended for patients with these characteristics.
From the clinico-pathologic stand point, EOGC preferentially occur in female gender presenting tumours with diffuse histology, multifocal appearance, proximal location
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by Grants from: Istituto Toscano Tumori (‘‘Gene expression profile and therapeutic implication in gastric cancer. From the clinical overview to the translational research’’; Grant ITT-2007) and The Portuguese Foundation for Science and Technology (FCT) [Grant number: PIC/IC/82923/2007, PTDC/SAU-GMG/72168/2006, PTDC/SAU-GMG/110785/2009, PTDC/SAU-ONC/110294/2009; PhD grant numbers: SFRH/BD/40090/2007-GC and SFRH/BD/41223/2007-HP; and Salary support from Program Ciência
References (64)
- et al.
Estimates of cancer incidence and mortality in Europe in 2008
Eur J Cancer
(2010) - et al.
Helicobacter pylori infection among offspring of patients with stomach cancer
Gastroenterology
(2000) - et al.
Early-onset gastric cancers have a different molecular expression profile than conventional gastric cancers
Mod Pathol
(2006) - et al.
Clinicopathologic characteristics of gastric cancer in a young patient population
J Gastrointest Surg
(2004) - et al.
Gastric carcinoma in children
J Pediatr Surg
(1993) - et al.
Early onset of gastric carcinoma and constitutional deletion of 18p
Cancer Genet Cytogenet
(1999) - et al.
E-cadherin and hereditary diffuse gastric cancer
Surgery
(2007) - et al.
E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients
Eur J Cancer
(2004) - et al.
Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression
Gastroenterology
(2009) Cadherins in cancer: implications for invasion and metastasis
Curr Opin Cell Biol
(1993)
The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene
Trends Biochem Sci
Gastric cancer in young patients
J Am Coll Surg
Gastric cancer: pathogenesis, screening, and treatment
Gastrointest Endosc Clin N Am
Estimating the world cancer burden: Globocan 2000
Int J Cancer
Trends of cancer mortality in Europe, 1955–1989: I. Digestive sites
Eur J Cancer
Global cancer statistics, 2002
CA Cancer J Clin
Interleukin-1 polymorphisms associated with increased risk of gastric cancer
Nature
Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma
J Natl Cancer Inst
Smoking status and gastric cancer risk: an updated meta-analysis of case-control studies published in the past ten years
Tumori
Red meat, family history, and increased risk of gastric cancer with microsatellite instability
Cancer Res
Early onset gastric cancer: on the road to unraveling gastric carcinogenesis
Curr Mol Med
Gastric cancer in young patients: demographic, clinicopathological, and prognostic factors in 92 patients
Ann Surg Oncol
Early-onset gastric carcinomas display molecular characteristics distinct from gastric carcinomas occurring at a later age
J Pathol
Gastric carcinoma in young adults in Japan
Anticancer Res
Alteration of E-cadherin-mediated adhesion protein is common, but microsatellite instability is uncommon in young age gastric cancers
Histopathology
Early gastric carcinoma in Japanese patients under 30 years of age
Br J Surg
A clinicopathological study in young patients with gastric carcinoma
J Surg Oncol
E-cadherin germline mutations in familial gastric cancer
Nature
Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands
Hum Mol Genet
Germline CDH1 deletions in hereditary diffuse gastric cancer families
Hum Mol Genet
Familial gastric cancer: overview and guidelines for management
J Med Genet
Cited by (63)
A comparison analysis of the somatic mutations in early-onset gastric cancer and traditional gastric cancer
2024, Clinics and Research in Hepatology and GastroenterologyCDH1 mutations in gastric cancers are not associated with family history
2020, Pathology Research and PracticeCitation Excerpt :A total of 122 CDH1 germline mutations has been reported worldwide, and the types of mutations include deletions, insertions and splice site, nonsense, and missense mutations [2]. Most previous studies identified germline mutations through polymerase chain reaction and sequencing [3–7], multiplex ligation-dependent probe amplification [8–11], or high-resolution melting analyses [12] using DNA from patients with familial gastric cancer (FGC), HDGC, or early-onset gastric cancer (EOGC). From these previous studies, CDH1 germline mutations were identified in 10 % of FGC cases [10,11], 0∼19 % of HDGC cases [3–5,8], and 0∼8.9 % [5,4–7,9] of EOGC cases with diffuse or mixed histologic types [6].
Germline mutations of the E-cadherin gene (CDH1) in early onset gastric cancer
2020, Seminars in OncologyCurrent advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications
2023, Journal of Experimental and Clinical Cancer ResearchRevisiting the Biological and Clinical Impact of CDH1 Missense Variants
2023, Hereditary Gastric and Breast Cancer Syndrome: CDH1: One Genotype with Multiple PhenotypesWorldwide CDH1 Germline Mutation Frequency
2023, Hereditary Gastric and Breast Cancer Syndrome: CDH1: One Genotype with Multiple Phenotypes