Hereditary diffuse gastric cancer (HDGC)

2009-07-01   Othman Saraj , Janusz A Jankowski 

Digestive Disease Centre, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom (OS, JAJ); Gastrointestinal Cancer Presentation Group, Oxford University, Oxford, United Kingdom (JAJ); GI Centre, Queen Marys Hospital, University of London, London, United Kingdom (JAJ)



Hereditary diffuse gastric cancer (HDGC)


Signet ring carcinoma or isolated cell type carcinoma.


Autosomal dominant with high penetrance (about 80%), average age of onset is in the 4th decade of life but it could be as early as the teens to the seventies. Germline mutations in CDH1 gene have been associated with this condition (Gayther et al., 1998; Guilford et al., 1998).





Criteria for diagnosis (Brooks-Wilson et al., 2004):
- Two or more cases of gastric cancer in a family, with at least one diffuse gastric cancer diagnosed before age 50 years.
- Three or more cases of gastric cancer in a family, diagnosed at any age, with at least one documented case of diffuse gastric cancer.
- An individual diagnosed with diffuse gastric cancer before 45 years of age.
- An individual diagnosed with both diffuse gastric cancer and lobular breast cancer (no other criteria met).
- One family member diagnosed with diffuse gastric cancer and another with lobular breast cancer (no other criteria met).
- One family member diagnosed with diffuse gastric cancer and another with signet ring colon cancer (no other criteria met).

Phenotype and clinics

HDGC forms less than 3% of all gastric cancers (Stone et al., 1999). It often affects younger people in contrast to the other types of gastric cancer. It consists of scattered clusters of poorly differentiated cells involving a large area of the stomach without a macroscopically recognisable margin or formation of a mass or ulcer (linitis plastica).
There is no known association between genotypic and phenotypic character of the disease (Kaurah and Huntsman, 2006).
Malignant risk: Four fifths of female carriers with CDH1 gene mutations are estimated to develop HDGC by age of 80 years with an additional 40% risk for lobular breast cancer, adding up to 90% for both cancers, while two thirds of males are expected to develop gastric cancer by the same age (Paul et al., 2001).


Aim of the management is: (1) Curative treatment through early detection and resection of the tumour completely, but unfortunately gastric cancer especially HDGC are usually incurable at presentation. (2) Identifying Germline mutation in CDH1 can provide help and support for family members who are unaffected but carrier of the genetic mutations by developing a plan to reduce the risk of cancer (Brooks-Wilson et al., 2004), through either (a) prophylactic gastrectomy which may be life saving as cancer cells have been detected in all resected stomach specimens in asymptomatic carriers (Huntsman et al., 2001), but with high morbidity and mortality (22-30% and 4-5% respectively (Kelsen et al., 2008)), or through (b) extensive biannual chromo endoscopic surveillance which has its limitation in detecting submucosal lesions in a normal looking mucosa, therefore the best preventive approach is yet to be established (Cisco et al., 2008).
In view of increase risk of colorectal cancer by 2-3 times and lobular breast cancer in females, surveillance colonoscopy every 3-5 years and regular MRI check of the breast may be required (Cisco et al., 2008; Porter et al., 2002).


Overall survival in gastric cancer is poor with 28% at 5 years and 20% at 10 years. However if the cancer is detected at early stages (i.e. confined to mucosa and submucosa), >90% will be alive at 5 years compare to 10-20% in advanced gastric cancer even when potentially curative surgery has been carried out (Kelsen et al., 2008; Leung et al., 2009).

Genes involved and Proteins




The gene consists of 16 exons and a 65-kb-long intron 2 that span around 100 kb (Berx et al., 1995).


CDH1 gene encodes for Cadherin protein which plays an important role in maintaining normal cell physiology like differentiation, growth, motility and tissue architecture through tight cell-cell adhesions (Conacci-Sorrell et al., 2002; Robertson and Jankowski, 2008).
Loss of cell adhesions have been noted in cancers for a long time. CDH1 suppression has been associated with poorly differentiated, aggressive, metastatic cancers. Mutation in E-cadherin is also associated with breast, colorectal cancers, thyroid, endometrial, ovarian, head and neck, skin, prostate, bladder cancer and other tumours (Birchmeier, 1995).


Germline mutations in CDH1 have been associated with HDGC. First mutations were described by Guilford et al. in three Maori families in New Zealand in 1998 (Guilford et al., 1998). Nowadays more than 50 different types of mutations have been described and new ones are emerging (Robertson and Jankowski, 2008). Types of mutations described are mainly truncating and missense mutations.
Up to 50% of families meeting the criteria above, which was set by the International Gastric cancer Linkage Consortium (IGCLC) in 2004, will have mutations in CDH1 (Brooks-Wilson et al., 2004).
Promoter methylation of the wild type allele in the mutated CDH1 is associated with loss of gene expression and might work as a \"second genetic hit\" predisposing to cancer and explain the absence of loss of heterozygosity in this condition (Grady et al., 2000).


Pubmed IDLast YearTitleAuthors
76014541995Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1).Berx G et al
77481701995E-cadherin as a tumor (invasion) suppressor gene.Birchmeier W et al
152350212004Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.Brooks-Wilson AR et al
187985462008Hereditary diffuse gastric cancer: implications of genetic testing for screening and prophylactic surgery.Cisco RM et al
119562332002The cadherin-catenin adhesion system in signaling and cancer.Conacci-Sorrell M et al
97516161998Identification of germ-line E-cadherin mutations in gastric cancer families of European origin.Gayther SA et al
109732392000Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer.Grady WM et al
95373251998E-cadherin germline mutations in familial gastric cancer.Guilford P et al
114194272001Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations.Huntsman DG et al
165018312006Genetics, pathology, and clinics of familial gastric cancer.Oliveira C et al
117291142001Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families.Pharoah PD et al
118966262002Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer.Porter TR et al
179250012008Genetics of gastroesophageal cancer: paradigms, paradoxes, and prognostic utility.Robertson EV et al
102063171999Low frequency of germline E-cadherin mutations in familial and nonfamilial gastric cancer.Stone J et al
187260702008The cell-cell adhesion molecule E-cadherin.van Roy F et al