E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients
Introduction
The incidence of gastric cancer has been decreasing in older patients, but in younger patients and cases with familial clustering the level remains stable [1]. Aggregation of gastric cancer within families is observed in approximately 10% of the cases [2], [3], but only 1–3% of gastric carcinomas arise as a result of inherited gastric cancer predisposition syndromes [4].
In 1999, clinical criteria for the hereditary diffuse gastric cancer (HDGC) syndrome were defined by the International Gastric Cancer Linkage Consortium (IGCLC) [5]. However, gastric cancer may also be seen as part of the tumour spectrum in other inherited cancer predisposition syndromes, such as: hereditary non-polyposis colorectal cancer syndrome (HNPCC), Li-Fraumeni syndrome (LFS), Familial Adenomatous Polyposis (FAP), Cowden syndrome and Peutz-Jeghers syndrome (PJS) [6], [7], [8], [9], [10].
The presence of germline CDH1 mutations in affected family members was shown to be, the genetic defect responsible for a proportion of families with HDGC as first described by Guilford and collaborators in 1998 [11]. Approximately one third of families with an aggregation of gastric cancer, fulfilling the IGCLC criteria for HDGC studied so far, show germline CDH1 mutations in affected individuals (reviewed in [12]). Most of these families carry truncating mutations, whereas a small percentage carry missense mutations [12].
Approximately two thirds of HDGC families remain genetically unexplained. In kindred negative for CDH1 germline mutations, other genes are probably involved. In some inherited predisposition syndromes characterised by a higher incidence of gastric cancer, germline mutations of different tumour-related genes have been demonstrated to segregate with the disease. HNPCC occurs due to inactivating alterations of mismatch repair genes (MMR) leading to instability at short tandem repeat sequences – microsatellites – microsatellite instability (MSI), a typical molecular manifestation of MMR deficiency in the tumour tissue of HNPCC patients [13]. In approximately 70% of Li-Fraumeni kindred, which occasionally present with gastric cancer cases, germline mutations in p53 are found [14]. SMAD4 has been found to be inactivated in a percentage of PJS, and knockout studies revealed the presence of foci of signet-ring carcinoma cells in the stomach of SMAD4 heterozygous mice [15]. Each of the aforementioned genes, as well as genes found to be inactivated in sporadic gastric cancer (like Caspase-10 [16]), remain good candidates for familial gastric cancer.
We have selected a series of Portuguese families with a positive history of gastric cancer (n=32), and a series of Portuguese early onset gastric cancer patients (n=23) and screened all probands for CDH1 germline mutations. In probands negative for CDH1, we have screened the entire coding sequence and splice-sites of several candidate genes, namely SMAD4, Caspase-10 and the mutational hotspots corresponding to exons 5–8 of p53. Whenever tumour tissue was available, we performed MSI analysis, and in MSI-positive cases hMLH1 and hMSH2 coding sequences were studied to exclude HNPCC.
Section snippets
Patients
The study protocol was reviewed and approved by the appropriate Ethics Committees and blood samples and family histories were obtained with informed consent. Thirty two families of Portuguese origin with a positive history of gastric cancer and 23 early onset gastric cancer patients (⩽45 years old) were studied (Table 1). Nine families fulfilled the IGCLC criteria for HDGC. Ten families had an index case with diffuse gastric cancer (FDGC). Three families had an index case with intestinal
Results
From the Portuguese families with an aggregation of gastric cancer, one out of 32 (3.1%) harboured a germline mutation in CDH1. This family (FGC#32) was one of the nine (11.1%) kindred that fulfilled the criteria for HDGC (Table 1, Table 2). The proband in this family was heterozygous for a missense mutation at position 1901 (C>T) in codon 634, leading to an amino acid substitution from Ala to Val (Fig. 1(a)). This germline mutation was identified in DNA isolated from paraffin-embedded normal
Discussion
We have collected a series of 55 patients of Portuguese origin which developed gastric cancer, either with a positive family history of gastric cancer or an early age of onset. The sole CDH1 germline mutation found was present in a family with HDGC. The CDH1 mutation found in family FGC#32 is a missense mutation (Ala634Val) and was identified in the 23 year old proband. This mutation was shown to harbour dramatic functional consequences in vitro [23]. Moreover, Vecsey-Semjen and colleagues [24]
Acknowledgements
We acknowledge all our colleagues who referred cases, and the patients and their families for generously participating in the research. This study was funded by Fundação para a Ciência e a Tecnologia, Portugal (Project POCTI/CBO/35374/2000; Project POCTI/MGI/35586/1999) and by Programa Operacional Ciência, Tecnologia e Inovação (POCTI), do QCA III.
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