Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer

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Human Molecular Genetics Pages 607-610

Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer
Introduction
Results
Discussion
Materials And Methods
   Patients
   Mutation detection
   Antibody staining
Acknowledgements
References

Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer

Frances M. Richards¹, Shane A. McKee², M. Helen Rajpar¹, Trevor R. P. Cole^1,2, D. Gareth R. Evans³, Janusz A. Jankowski⁴, Carole McKeown^1,2, D. Scott A. Sanders⁵ and Eamonn R. Maher^1,2,*

¹Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham, The Medical School, Birmingham B15 2TT, UK, ²West Midlands Regional Clinical Genetics Service, Birmingham Women’s Hospital, Birmingham B15 2TG, UK, ³Department of Medical Genetics, St Mary’s Hospital, Manchester M13 0JH, UK and ⁴Department of Medicine and ⁵Department of Pathology, University of Birmingham, Birmingham B15 2TT, UK

Received November 5, 1998; Revised and Accepted January 15, 1999

Inherited mutations in the E-cadherin gene (CDH1) were described recently in three Maori kindreds with familial gastric cancer. Familial gastric cancer is genetically heterogeneous and it is not clear what proportion of gastric cancer susceptibility in non-Maori populations is due to germline CDH1 mutations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of all 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 years; or (ii) three or more cases of gastric cancer. Novel germline CDH1 mutations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. We have confirmed that germline mutations in the CDH1 gene cause familial gastric cancer in non-Maori populations. However, only a minority of familial gastric cancers can be accounted for by CDH1 mutations. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.

INTRODUCTION

Gastric cancer causes >400 000 deaths worldwide every year. As with many common cancers both environmental and genetic factors have been implicated in the pathogenesis of gastric cancer (1,2). Helicobacter pylori infection is a recognized cause of gastric cancer and the falling incidence of gastric cancer in the Western world has been attributed to dietary changes. Approximately 10% of gastric cancers show familial clustering and case control studies have identified a 3-fold increased risk of the disease in the first degree relatives of affected individuals (3). Although this does not necessarily indicate a genetic cause, striking examples of dominantly inherited predisposition to gastric cancer (including Napoleon Bonaparte’s family) have been reported (4). In addition, a number of dominantly inherited familial cancer syndromes are characterized by gastric cancer susceptibility. Thus, germline mutations in mismatch repair genes (e.g. MSH2 and MLH1) which cause hereditary non-polyposis colon cancer syndrome (HNPCC) are associated with susceptibility to gastric cancer (5,6) and germline p53 mutations may cause gastric cancer rarely (7). Although the cumulative risk for gastric cancer in HNPCC has been estimated as high as 19% (8), in a clinical study of 25 English familial gastric cancer kindreds, we found that most families did not fulfil diagnostic criteria for HNPCC (9). This suggested that most familial gastric cancer was caused by other genes. Recently, Guilford et al. (10) reported germline mutations in the E-cadherin gene (CDH1) in three familial gastric cancer kindreds of Maori origin from New Zealand. In view of the genetic heterogeneity of gastric cancer we analysed eight UK gastric cancer kindreds to determine: (i) if germline CDH1 mutations occurred in the UK population; and (ii) the phenotypic expression of CDH1 mutations.

RESULTS

The clinical and pathological features of the eight kindreds studied are summarized in Table 1. Gastric cancer only was present in three kindreds. All families were of Caucasian (British or Irish) origin.

Table 1. Details of gastric cancer families screened for CDH1 mutations, including the number of individuals affected with gastric cancer and the age at diagnosis

Family ID Number affected Generations Mean age (range) Diffuse type Other tumours in first degree relatives of patients (age in years) CDH-1 mutation

A 6 2 50 (34-69) + Lung (NS), rectum (30) A(49-2)G (splice junction)

B 3 3 38 (27-50) + No G59A (nonsense)

C 4 3 50 (31-73) + Oesophagus (66), colon (78), prostate (80), spinal (26), brain (26) Not found

D 2 1 40 (30-49) NS Pancreas (62, in proband), rectum (64), prostate (63), breast (34) Not found

E 2 2 48 (36-59) NS Breast (39) Not found

F 3 2 49 (42-59) NS No Not found

G 4 2 55 (40-74) + No Not found

H 6 2 51 (41-58) NS Throat (NS) Not found

The type of gastric cancer (whether diffuse type or not) was ascertained from histopathology reports.
NS, not specified.

Screening all 16 exons of the CDH1 gene by PCR-SSCP and direct sequencing revealed a germline CDH1 gene mutation in two kindreds (Fig. 1). In family A (individual III-2), an A->G transition at position 49-2 was identified in the splice acceptor site at the start of exon 2. This A (2 bases before the exon) is 100% conserved in mammalian splice sites and abolition of this splice site is predicted to truncate the protein after codon 16. In family B, a germline G59A transition was identified in exon 2, substituting a stop codon for a tryptophan at codon 20. Both mutations are predicted to truncate the E-cadherin gene product in the signal peptide domain which is cleaved from the N-terminus of the mature protein. No germline mutations were identified in the remaining families, but the index cases in families C and E-H were heterozygous for a silent C/T (HpaII) polymorphism at nt 2076 (exon 13), excluding a germline deletion in this part of the gene.

   a

   b

   c

Figure 1. (a) Pedigrees of gastric cancer families A and B. Solid symbols represent gastric cancer cases, the half-shaded symbol represents carcinoma of the rectum. Unaffected individuals have been omitted to maintain confidentiality. Numbers represent the age at diagnosis of cancer in affected individuals. The individual initially screened for mutations in each family is arrowed. (b) Sequence of CDH1 mutation in patient B. Direct sequencing of exon 2 PCR product with forward primer (using ABI 377), from a normal individual and from patient B showing a G59A transition (arrow). Primer sequences and PCR conditions for CDH1 exons were taken from Berx et al. (25). (c) Confirmation of CDH1 mutations by restriction enzyme digestion of DNA. Exon 2 PCR products (199 bp) from blood DNA of patients A (III-2) and B and a normal individual (N), plus DNA from normal colon (C) and adenocarcinoma of the rectum (T) of patient A (III-1) and normal stomach (S) and gastric adenocarcinoma (T) from patient A (II-4) were digested with AvaI or DdeI, separated on an 8% polyacrylamide, 0.5× TBE gel and silver stained. The A(49-2)G mutation in family A creates an AvaI site producing 169 and 30 bp fragments. The G59A mutation in family B creates a DdeI site producing 157 and 42 bp fragments.

Family B contained three cases of gastric cancer (two diagnosed under 50 years) and no reports of extragastric cancers. Family A included six cases of gastric cancer (three under 50 years) and one individual (III-1) with adenocarcinoma of the rectum (aged 30 years). To determine if colorectal carcinoma susceptibility is associated with a germline CDH1 mutation, DNA samples from individual III-1 were screened for the germline A(49-2)G mutation and the mutation was present both in her normal colon and in the moderately differentiated rectal adenocarcinoma (Fig. 1). The germline mutation was also present in the normal stomach and gastric carcinoma from individual II-4. This gastric adenocarcinoma was poorly differentiated with focally diffuse/signet ring cell morphology. There was no evidence of deletion of the wild-type CDH1 allele in either of the tumours, either by analysis of the exon 2 PCR products themselves (Fig. 1) or by analysis of loss of heterozygosity (LOH) with the closely linked marker D16S752 (data not shown). However, the high proportion of normal stromal tissue surrounding islands of tumour cells (despite dissection of the tumour sections prior to DNA extraction) may have obscured any LOH. Nevertheless, immunostaining sections of both the gastric and rectal tumours with anti-E-cadherin monoclonal antibody HECD-1 clearly demonstrated E-cadherin protein expression (data not shown). The subcellular localization of the protein was heterogeneous in both tumours: it was expressed at apparently normal levels (compared with adjacent normal tissue) and localized mostly at the cell membrane (as in normal glandular epithelium) in better differentiated regions; in poorly differentiated regions it was present at similar levels but mainly in the cytoplasm of the tumour cells, and at the advancing front of each tumour it was also cytoplasmic, but at much reduced levels. This heterogeneous pattern was also observed in tumour sections from families where an E-cadherin mutation was not detected and is consistent in sporadic gastric carcinomas. Analysis for tumour microsatellite instability using two mononucleotide markers (BAT26 and BAT40) was negative in a tumour from kindreds A, C and H.

DISCUSSION

We have confirmed that germline CDH1 mutations cause familial gastric cancer in non-Maori populations. Furthermore, the finding of very early onset colorectal cancer in a CDH1 mutation carrier suggests that CDH1 mutations also predispose to extragastric tumours. Recently, Gayther et al. (11) have also reported three European kindreds with germline CDH1 mutations and familial gastric cancer. Thus, a total of eight different germline CDH1 mutations have now been identified worldwide in familial gastric cancer. All the mutations reported so far are predicted to be protein truncating and they are scattered throughout the gene from exon 2 to exon 15. E-cadherin is a homophilic cell adhesion molecule which is important for establishing cell polarity and maintaining normal tissue morphology and cellular differentiation. E-cadherin acts as a cell-cell specific recognition receptor in many tissues, maintaining epithelial structure. Loss of E-cadherin expression is associated with tumorigenesis in many human cancers (12; see also below), including gastric (13-15), but this loss is usually a late event associated with metastasis in advanced stage tumours, suggesting that E-cadherin acts as an ‘invasion suppressor’. The germline CDH1 mutations identified by ourselves and others (10,11) suggest that E-cadherin may also have a role as a tumour suppressor earlier in the multi-step process of tumorigenesis. If E-cadherin functions as a classical tumour suppressor gene in accordance with Knudson’s two-hit hypothesis (16) then loss or inactivation of the remaining normal CDH1 allele would be an initiating event in tumorigenesis in individuals carrying a germline mutation. The ‘second hit’ to a tumour suppressor gene is frequently deletion of the whole gene and a large part of the chromosome (detected as LOH) or silencing of the gene by promoter methylation, which has been observed for CDH1 in sporadic tumours (17). E-cadherin protein was clearly detected in gastric and colorectal tumour cells from family A, using an antibody which detects an HAV peptide in the first extracellular repeat domain of E-cadherin. Any protein produced from the allele with the germline mutation would be predicted to include only 17 amino acids of the N-terminal signal peptide, lacking the extracellular domain, suggesting that there has not been either deletion or promoter silencing of the second CDH1 allele in these tumours. These findings would suggest that: (i) the germline mutations identified have a dominant-negative effect; (ii) a 50% reduction in E-cadherin function is sufficient to promote tumorigenesis; or (iii) the wild-type allele in the tumour tissue contains a missense mutation, an in-frame deletion or a 3[prime] truncating mutation. It has previously been shown that some mutated forms of E-cadherin protein can be detected by antibody staining (13). Our results demonstrate that loss of membranous staining of E-cadherin is not an early event in tumours from patients with germline CDH1 mutations and suggest that E-cadherin antibody staining of tumours will not be a reliable screening technique to identify individuals with a germline E-cadherin mutation. All eight families with germline CDH1 mutations reported to date have diffuse or signet cell gastric cancers (10,11). Somatic CDH1 mutations in gastric cancer were initially reported in diffuse type tumours (13), but we did not find germline CDH1 mutations in two other families with diffuse gastric cancer. Our mutation analysis strategy would not detect all types of CDH1 mutations, but the finding that only 25% of all kindreds had CDH1 mutations is consistent with genetic heterogeneity and other gastric cancer susceptibility genes. We note that Gayther et al. (11) excluded linkage to E-cadherin in one family. These preliminary results suggest an association between familial diffuse-type gastric cancer and CDH1 mutations. However, both diffuse and intestinal familial gastric cancers have been reported (18) and in many tumours there are in fact elements of both these histological types, so it may be premature to conclude that there is a clear genotype-cell type correlation.

The optimum management of CDH1 mutation carriers should be determined from multicentre studies of the penetrance and phenotypic expression of CDH1 mutations. Loss of E-cadherin has been implicated in the pathogenesis of several non-familial human cancers including gastric, colorectal, breast, gynaecological and prostate (13,17,19,20). E-cadherin is further implicated in the pathogenesis of colorectal cancer by its interaction with the APC and [beta]-catenin gene products (21). APC is the major ‘gatekeeper’ tumour suppressor gene for colorectal cancer, and germline APC mutations cause familial polyposis coli (22). Our finding that one E-cadherin gene carrier developed early onset colorectal cancer allied to the occurrence of colorectal cancer in two gene carriers (one at the age of 30 years) reported by Guilford et al. (10), therefore has important implications for the molecular genetic analysis of colorectal cancer susceptibility. Thus, although CDH1 has not been implicated previously in inherited colorectal cancer susceptibility, our observations might suggest CDH1 as a candidate gene for familial or early onset colorectal cancer. Although germline mismatch repair genes account for a significant proportion of familial and early onset colorectal cancers (<35 years), many cases do not show clinical or molecular evidence of HNPCC, suggesting the involvement of non-mismatch repair genes (23,24). In family A (individual II-1), there was evidence of non-penetrance despite early onset gastric and colorectal cancer in other relatives. This suggests that germline CDH1 mutations could present with apparently isolated gastric or colorectal cancer and that further studies are indicated to determine in greater detail the contribution of CDH1 mutations to early onset and familial gastric and colorectal cancer.

MATERIALS AND METHODS

Patients

Patients with familial gastric cancer were identified through the Regional Clinical Genetics Services and DNA was extracted from blood of one affected individual from each of eight families. Families were selected according to the following criteria: (i) two or more cases of gastric cancer (one of which was diagnosed before age 50 years); or (ii) three cases of gastric cancer at any age. Families with HNPCC were excluded.

Mutation detection

Germline DNA was screened for CDH1 mutations by PCR amplification of each exon followed by single strand conformation polymorphism (SSCP) analysis on 8% polyacrylamide, 5% glycerol, 0.5× TBE gels run at room temperature, then silver stained. Primers for PCR amplification of each exon were as described by Berx et al. (25), with the exceptions of the reverse primers for exon 4 [from Dr S. Gayther, University of Cambridge (11)] and exon 2 (ecad2R1, 5[prime]-TTTCCAACCCCTCCCTAC-3[prime], 199 bp product) and primers for exon 1 (ecad1F1, 5[prime]-AGACTCCAGCCCGCTCCAG-3[prime] and ecad1R1, 5[prime]-AGCTTGCGGCCCGAATGC-3[prime], 182 bp product) and exon 5 (ecad5F2, 5[prime]-GTGTTGGGATCCTTCTTTAC-3[prime] and ecad5R2, 5[prime]-ATCCAGCATGGGTTGACC-3[prime], 279 bp product). PCR was performed in an OmnE thermal cycler (Hybaid, Ashford, UK) in a buffer of 10 mM Tris-HCl pH 8.8, 50 mM KCl, 0.01% gelatin, 0.2 mM dNTPs, 1.5 mM MgCl₂ (exons 4, 5 and 13) or 2 mM MgCl₂, with 5 pmol each primer plus 0.3 U Taq polymerase (Life Technologies, Paisley, UK) and 100 ng DNA/15 µl reaction. Betaine (1 M) was added to exon 1 PCRs. Annealing temperatures were 53°C for exons 2, 4, 5 and 8, 55°C for exons 6 and 9, 58°C for exon 13 and 60°C for exons 1, 3, 7, 10-12 and 14-16.

Exons containing any possible band shifts were sequenced in both directions on an ABI 377 semi-automated DNA sequencer using an ABI Prism dRhodamine Terminator cycle sequencing kit, after purification of PCR products with Wizard PCR Preps (Promega, Southampton, UK).

Restriction enzyme digestions to confirm mutations were performed on PCR-amplified exons according to the manufacturer’s instructions (Life Technologies), and analysed on 8% polyacrylamide gels.

DNA extraction from paraffin-embedded colon, stomach and tumour tissue was performed according to the method of Iwamoto et al. (26). Microdissection of tumour sections was performed prior to extraction to maximize the proportion of tumour cells.

Antibody staining

Five micron sections of paraffin-embedded tissues were cut and mounted on APES prepared slides, microwave pre-treated and immunostained using a standard indirect ABC technique. E-cadherin antibody (HECD-1; 200 µg/µl) (Affiniti Research Products, Exeter, UK) was used at 1:100 dilution.

ACKNOWLEDGEMENTS

We thank Ken Hosie and Shirley Hodgson for providing families and Loveena Verma for technical assistance. This work was supported by the British Digestive Foundation and the Royal Society.

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*To whom correspondence should be addressed at: Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham, The Medical School, Birmingham B15 2TT, UK. Tel: +44 121 627 2741; Fax: +44 121 627 2618; Email: ermaher@hgmp.mrc.ac.uk

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Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients
J. Med. Genet., June 1, 2004; 41(6): e89 - e89.
[Full Text] [PDF]

F. Graziano, B. Humar, and P. Guilford
The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice
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[Abstract] [Full Text] [PDF]

M. Kremer, L. Quintanilla-Martinez, M. Fuchs, A. Gamboa-Dominguez, S. Haye, H. Kalthoff, E. Rosivatz, C. Hermannstadter, R. Busch, H. Hofler, et al.
Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis
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[Abstract] [Full Text] [PDF]

Y. Wang, J.-P. Song, M. Ikeda, K. Shinmura, J. Yokota, and H. Sugimura
Ile-Leu Substitution (I415L) in Germline E-cadherin Gene (CDH1) in Japanese Familial Gastric Cancer
Jpn. J. Clin. Oncol., January 1, 2003; 33(1): 17 - 20.
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N. Okazaki, N. Takahashi, S.-i. Kojima, Y. Masuho, and H. Koga
Protocadherin LKC, a new candidate for a tumor suppressor of colon and liver cancers, its association with contact inhibition of cell proliferation
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Targeted inactivation of CTNNB1 reveals unexpected effects of beta -catenin mutation
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Association of E-Cadherin Germ-Line Alterations with Prostate Cancer
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[Abstract] [Full Text] [PDF]

P. G. Corn, E. I. Heath, R. Heitmiller, F. Fogt, A. A. Forastiere, J. G. Herman, and T.-T. Wu
Frequent Hypermethylation of the 5' CpG Island of E-Cadherin in Esophageal Adenocarcinoma
Clin. Cancer Res., September 1, 2001; 7(9): 2765 - 2769.
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J D Chen, S Kearns, T Porter, F M Richards, E R Maher, and B T Teh
MET mutation and familial gastric cancer
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D. G. Huntsman, F. Carneiro, F. R. Lewis, P. M. MacLeod, A. Hayashi, K. G. Monaghan, R. Maung, R. Seruca, C. E. Jackson, and C. Caldas
Early Gastric Cancer in Young, Asymptomatic Carriers of Germ-Line E-Cadherin Mutations
N. Engl. J. Med., June 21, 2001; 344(25): 1904 - 1909.
[Abstract] [Full Text] [PDF]

P. Peltomaki
Deficient DNA mismatch repair: a common etiologic factor for colon cancer
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[Abstract] [Full Text] [PDF]

L. VERMA, T. R PORTER, F. M RICHARDS, M H. RAJPAR, D G. R EVANS, F. MACDONALD, and E. R MAHER
Germline mutation analysis of the transforming growth factor {beta} receptor type II (TGFBR2) and E-cadherin (CDH1) genes in early onset and familial colorectal cancer
J. Med. Genet., February 1, 2001; 38(2): 7e - 7.
[Full Text]

E. AVIZIENYTE, V. LAUNONEN, R. SALOVAARA, T. KIVILUOTO, and L. A AALTONEN
E-cadherin is not frequently mutated in hereditary gastric cancer
J. Med. Genet., January 1, 2001; 38(1): 49 - 52.
[Full Text]

J.-G. Park, H.-K. Yang, W. H. Kim, C. Caldas, J. Yokota, and P. J. Guilford
Report on the First Meeting of the International Collaborative Group on Hereditary Gastric Cancer
J Natl Cancer Inst, November 1, 2000; 92(21): 1781 - 1782.
[Full Text] [PDF]

P. G. Corn, B. D. Smith, E. S. Ruckdeschel, D. Douglas, S. B. Baylin, and J. G. Herman
E-Cadherin Expression Is Silenced by 5' CpG Island Methylation in Acute Leukemia
Clin. Cancer Res., November 1, 2000; 6(11): 4243 - 4248.
[Abstract] [Full Text] [PDF]

H C Kim, J M D Wheeler, J C Kim, M Ilyas, N E Beck, B S Kim, K C Park, and W F Bodmer
The E-cadherin gene (CDH1) variants T340A and L599V in gastric and colorectal cancer patients in Korea
Gut, August 1, 2000; 47(2): 262 - 267.
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Y. J. Park, K.-H. Shin, and J.-G. Park
Risk of Gastric Cancer in Hereditary Nonpolyposis Colorectal Cancer in Korea
Clin. Cancer Res., August 1, 2000; 6(8): 2994 - 2998.
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L.-C. Li, R. M. Chui, M. Sasaki, K. Nakajima, G. Perinchery, H. C. Au, D. Nojima, P. Carroll, and R. Dahiya
A Single Nucleotide Polymorphism in the E-cadherin Gene Promoter Alters Transcriptional Activities
Cancer Res., February 1, 2000; 60(4): 873 - 876.
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C. Caldas, F. Carneiro, H. T Lynch, J. Yokota, G. L Wiesner, S. M Powell, F. R Lewis, D. G Huntsman, P. D P Pharoah, J. A Jankowski, et al.
Familial gastric cancer: overview and guidelines for management*
J. Med. Genet., December 1, 1999; 36(12): 873 - 880.
[Abstract] [Full Text] [PDF]

G. Keller, H. Vogelsang, I. Becker, J. Hutter, K. Ott, S. Candidus, T. Grundei, K.-F. Becker, J. Mueller, J. R. Siewert, et al.
Diffuse Type Gastric and Lobular Breast Carcinoma in a Familial Gastric Cancer Patient with an E-Cadherin Germline Mutation
Am. J. Pathol., August 1, 1999; 155(2): 337 - 342.
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Family ID	Number affected	Generations	Mean age (range)	Diffuse type	Other tumours in first degree relatives of patients (age in years)	CDH-1 mutation
A	6	2	50 (34-69)	+	Lung (NS), rectum (30)	A(49-2)G (splice junction)
B	3	3	38 (27-50)	+	No	G59A (nonsense)
C	4	3	50 (31-73)	+	Oesophagus (66), colon (78), prostate (80), spinal (26), brain (26)	Not found
D	2	1	40 (30-49)	NS	Pancreas (62, in proband), rectum (64), prostate (63), breast (34)	Not found
E	2	2	48 (36-59)	NS	Breast (39)	Not found
F	3	2	49 (42-59)	NS	No	Not found
G	4	2	55 (40-74)	+	No	Not found
H	6	2	51 (41-58)	NS	Throat (NS)	Not found

				C. Oliveira, J. Senz, P. Kaurah, H. Pinheiro, R. Sanges, A. Haegert, G. Corso, J. Schouten, R. Fitzgerald, H. Vogelsang, et al. Germline CDH1 deletions in hereditary diffuse gastric cancer families Hum. Mol. Genet., May 1, 2009; 18(9): 1545 - 1555. [Abstract] [Full Text] [PDF]

				F Carneiro, C Oliveira, G Suriano, and R Seruca Molecular pathology of familial gastric cancer, with an emphasis on hereditary diffuse gastric cancer J. Clin. Pathol., January 1, 2008; 61(1): 25 - 30. [Abstract] [Full Text] [PDF]

				H. Yamada, K. Shinmura, K. Okudela, M. Goto, M. Suzuki, K. Kuriki, T. Tsuneyoshi, and H. Sugimura Identification and characterization of a novel germ line p53 mutation in familial gastric cancer in the Japanese population Carcinogenesis, September 1, 2007; 28(9): 2013 - 2018. [Abstract] [Full Text] [PDF]

				E. Zagorowicz and J. Jankowski Molecular changes in the progression of Barrett's oesophagus Postgrad. Med. J., August 1, 2007; 83(982): 529 - 535. [Abstract] [Full Text] [PDF]

				P. Kaurah, A. MacMillan, N. Boyd, J. Senz, A. De Luca, N. Chun, G. Suriano, S. Zaor, L. Van Manen, C. Gilpin, et al. Founder and Recurrent CDH1 Mutations in Families With Hereditary Diffuse Gastric Cancer JAMA, June 6, 2007; 297(21): 2360 - 2372. [Abstract] [Full Text] [PDF]

				W. C. Reinhold, M. A. Reimers, A. K. Maunakea, S. Kim, S. Lababidi, U. Scherf, U. T. Shankavaram, M. S. Ziegler, C. Stewart, H. Kouros-Mehr, et al. Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells Mol. Cancer Ther., February 1, 2007; 6(2): 391 - 403. [Abstract] [Full Text] [PDF]

				J T Bacani, M Soares, R Zwingerman, N di Nicola, J Senz, R Riddell, D G Huntsman, and S Gallinger CDH1/E-cadherin germline mutations in early-onset gastric cancer J. Med. Genet., November 1, 2006; 43(11): 867 - 872. [Abstract] [Full Text] [PDF]

				T Frebourg, C Oliveira, P Hochain, R Karam, S Manouvrier, C Graziadio, M Vekemans, A Hartmann, S Baert-Desurmont, C Alexandre, et al. Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer J. Med. Genet., February 1, 2006; 43(2): 138 - 142. [Abstract] [Full Text] [PDF]

				C. Oliveira, R. Seruca, and F. Carneiro Genetics, Pathology, and Clinics of Familial Gastric Cancer International Journal of Surgical Pathology, January 1, 2006; 14(1): 21 - 33. [Abstract] [PDF]

				G. Suriano, S. Yew, P. Ferreira, J. Senz, P. Kaurah, J. M. Ford, T. A. Longacre, J. A. Norton, N. Chun, S. Young, et al. Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management Clin. Cancer Res., August 1, 2005; 11(15): 5401 - 5409. [Abstract] [Full Text] [PDF]

				T. Kamoto, Y. Isogawa, Y. Shimizu, S. Minamiguchi, H. Kinoshita, Y. Kakehi, K. Mitsumori, S. Yamamoto, T. Habuchi, T. Kato, et al. Association of a Genetic Polymorphism of the E-cadherin Gene with Prostate Cancer in a Japanese Population Jpn. J. Clin. Oncol., March 1, 2005; 35(3): 158 - 161. [Abstract] [Full Text] [PDF]

				K M Sweet and H T Lynch Genetic aetiology of diffuse gastric cancer: so near, yet so far J. Med. Genet., July 1, 2004; 41(7): 481 - 483. [Full Text] [PDF]

				A R Brooks-Wilson, P Kaurah, G Suriano, S Leach, J Senz, N Grehan, Y S N Butterfield, J Jeyes, J Schinas, J Bacani, et al. Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria J. Med. Genet., July 1, 2004; 41(7): 508 - 517. [Abstract] [Full Text] [PDF]

				R C Fitzgerald and C Caldas Clinical implications of E-cadherin associated hereditary diffuse gastric cancer Gut, June 1, 2004; 53(6): 775 - 778. [Abstract] [Full Text] [PDF]

				G Keller, H Vogelsang, I Becker, S Plaschke, K Ott, G Suriano, A R Mateus, R Seruca, K Biedermann, D Huntsman, et al. Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients J. Med. Genet., June 1, 2004; 41(6): e89 - e89. [Full Text] [PDF]

				F. Graziano, B. Humar, and P. Guilford The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice Ann. Onc., December 1, 2003; 14(12): 1705 - 1713. [Abstract] [Full Text] [PDF]

				M. Kremer, L. Quintanilla-Martinez, M. Fuchs, A. Gamboa-Dominguez, S. Haye, H. Kalthoff, E. Rosivatz, C. Hermannstadter, R. Busch, H. Hofler, et al. Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis Carcinogenesis, December 1, 2003; 24(12): 1879 - 1886. [Abstract] [Full Text] [PDF]

				Y. Wang, J.-P. Song, M. Ikeda, K. Shinmura, J. Yokota, and H. Sugimura Ile-Leu Substitution (I415L) in Germline E-cadherin Gene (CDH1) in Japanese Familial Gastric Cancer Jpn. J. Clin. Oncol., January 1, 2003; 33(1): 17 - 20. [Abstract] [Full Text] [PDF]

				N. Okazaki, N. Takahashi, S.-i. Kojima, Y. Masuho, and H. Koga Protocadherin LKC, a new candidate for a tumor suppressor of colon and liver cancers, its association with contact inhibition of cell proliferation Carcinogenesis, July 1, 2002; 23(7): 1139 - 1148. [Abstract] [Full Text] [PDF]

				T. A. Chan, Z. Wang, L. H. Dang, B. Vogelstein, and K. W. Kinzler Targeted inactivation of CTNNB1 reveals unexpected effects of beta -catenin mutation PNAS, June 11, 2002; 99(12): 8265 - 8270. [Abstract] [Full Text] [PDF]

				T. Ikonen, M. Matikainen, N. Mononen, E.-R. Hyytinen, H. J. Helin, S. Tommola, T. L. J. Tammela, E. Pukkala, J. Schleutker, O.-P. Kallioniemi, et al. Association of E-Cadherin Germ-Line Alterations with Prostate Cancer Clin. Cancer Res., November 1, 2001; 7(11): 3465 - 3471. [Abstract] [Full Text] [PDF]

				P. G. Corn, E. I. Heath, R. Heitmiller, F. Fogt, A. A. Forastiere, J. G. Herman, and T.-T. Wu Frequent Hypermethylation of the 5' CpG Island of E-Cadherin in Esophageal Adenocarcinoma Clin. Cancer Res., September 1, 2001; 7(9): 2765 - 2769. [Abstract] [Full Text] [PDF]

				J D Chen, S Kearns, T Porter, F M Richards, E R Maher, and B T Teh MET mutation and familial gastric cancer J. Med. Genet., August 1, 2001; 38(8): e26 - 26. [Full Text] [PDF]

				D. G. Huntsman, F. Carneiro, F. R. Lewis, P. M. MacLeod, A. Hayashi, K. G. Monaghan, R. Maung, R. Seruca, C. E. Jackson, and C. Caldas Early Gastric Cancer in Young, Asymptomatic Carriers of Germ-Line E-Cadherin Mutations N. Engl. J. Med., June 21, 2001; 344(25): 1904 - 1909. [Abstract] [Full Text] [PDF]

				P. Peltomaki Deficient DNA mismatch repair: a common etiologic factor for colon cancer Hum. Mol. Genet., April 1, 2001; 10(7): 735 - 740. [Abstract] [Full Text] [PDF]

				L. VERMA, T. R PORTER, F. M RICHARDS, M H. RAJPAR, D G. R EVANS, F. MACDONALD, and E. R MAHER Germline mutation analysis of the transforming growth factor {beta} receptor type II (TGFBR2) and E-cadherin (CDH1) genes in early onset and familial colorectal cancer J. Med. Genet., February 1, 2001; 38(2): 7e - 7. [Full Text]

				E. AVIZIENYTE, V. LAUNONEN, R. SALOVAARA, T. KIVILUOTO, and L. A AALTONEN E-cadherin is not frequently mutated in hereditary gastric cancer J. Med. Genet., January 1, 2001; 38(1): 49 - 52. [Full Text]

				J.-G. Park, H.-K. Yang, W. H. Kim, C. Caldas, J. Yokota, and P. J. Guilford Report on the First Meeting of the International Collaborative Group on Hereditary Gastric Cancer J Natl Cancer Inst, November 1, 2000; 92(21): 1781 - 1782. [Full Text] [PDF]

				P. G. Corn, B. D. Smith, E. S. Ruckdeschel, D. Douglas, S. B. Baylin, and J. G. Herman E-Cadherin Expression Is Silenced by 5' CpG Island Methylation in Acute Leukemia Clin. Cancer Res., November 1, 2000; 6(11): 4243 - 4248. [Abstract] [Full Text] [PDF]