Download Cancer Prone Disease Section Hereditary diffuse gastric cancer (HDGC)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Hereditary diffuse gastric cancer (HDGC)
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 Mary's Hospital, University of London, London, United Kingdom (JAJ)
Published in Atlas Database: July 2009
Online updated version : http://AtlasGeneticsOncology.org/Kprones/HeredGastrCarcID10078.html
DOI: 10.4267/2042/44789
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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).
Identity
Alias: Signet ring carcinoma or isolated cell type
carcinoma.
Inheritance: 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).
Clinics
Note
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).
Treatment
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 (BrooksWilson 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
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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(6)
599
Hereditary diffuse gastric cancer (HDGC)
Saraj O, Jankowski JA
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).
the breast may be required (Cisco et al., 2008; Porter et
al., 2002).
Prognosis
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).
References
Berx G, Staes K, van Hengel J, Molemans F, Bussemakers
MJ, van Bokhoven A, van Roy F. Cloning and characterization
of the human invasion suppressor gene E-cadherin (CDH1).
Genomics. 1995 Mar 20;26(2):281-9
Genes involved and proteins
Birchmeier W. E-cadherin as a tumor (invasion) suppressor
gene. Bioessays. 1995 Feb;17(2):97-9
CDH1
Gayther SA, Gorringe KL, Ramus SJ, Huntsman D, Roviello F,
Grehan N, Machado JC, Pinto E, Seruca R, Halling K,
MacLeod P, Powell SM, Jackson CE, Ponder BA, Caldas C.
Identification of germ-line E-cadherin mutations in gastric
cancer families of European origin. Cancer Res. 1998 Sep
15;58(18):4086-9
Location
16q22.1
DNA/RNA
Description: The gene consists of 16 exons and a 65kb-long intron 2 that span around 100 kb (Berx et al.,
1995).
Protein
Description: E cadherin is a transmembrane calcium
dependant glycoprotein (728 AA) with cytoplasmic
domain which binds to actin cytoskeleton via catenins
(catenin alpha, catenin beta and catenin gamma), single
transmembrane domain, and extracellular domains
which adhere to neighbouring cells and form a tight
homophilic bond which is an important part in cell-cell
adhesions, tissue architecture, cell differentiations and
proliferations (Conacci-Sorrell et al., 2002; Roy and
Berx, 2008).
Function: 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).
Mutations
Germinal: 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).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(6)
Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N,
Harawira P, Taite H, Scoular R, Miller A, Reeve AE. Ecadherin germline mutations in familial gastric cancer. Nature.
1998 Mar 26;392(6674):402-5
Stone J, Bevan S, Cunningham D, Hill A, Rahman N, Peto J,
Marossy A, Houlston RS. Low frequency of germline Ecadherin mutations in familial and nonfamilial gastric cancer. Br
J Cancer. 1999 Apr;79(11-12):1935-7
Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch
H, Wiesner G, Ferguson K, Eng C, Park JG, Kim SJ,
Markowitz S. Methylation of the CDH1 promoter as the second
genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000
Sep;26(1):16-7
Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi
A, Monaghan KG, Maung R, Seruca R, Jackson CE, Caldas C.
Early gastric cancer in young, asymptomatic carriers of germline E-cadherin mutations. N Engl J Med. 2001 Jun
21;344(25):1904-9
Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer
and breast cancer in CDH1 (E-cadherin) mutation carriers from
hereditary diffuse gastric cancer families. Gastroenterology.
2001 Dec;121(6):1348-53
Conacci-Sorrell M, Zhurinsky J, Ben-Ze'ev A. The cadherincatenin adhesion system in signaling and cancer. J Clin Invest.
2002 Apr;109(8):987-91
Porter TR, Richards FM, Houlston RS, Evans DG, Jankowski
JA, Macdonald F, Norbury G, Payne SJ, Fisher SA, Tomlinson
I, Maher ER. Contribution of cyclin d1 (CCND1) and Ecadherin (CDH1) polymorphisms to familial and sporadic
colorectal cancer. Oncogene. 2002 Mar 14;21(12):1928-33
Brooks-Wilson AR, Kaurah P, Suriano G, Leach S, Senz J,
Grehan N, Butterfield YS, Jeyes J, Schinas J, Bacani J, Kelsey
M, Ferreira P, MacGillivray B, MacLeod P, Micek M, Ford J,
Foulkes W, Australie K, Greenberg C, LaPointe M, 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. 2004 Jul;41(7):508-17
Kaurah P, Huntsman DG.. Hereditary Diffuse Gastric Cancer.
GeneReviews 2006.
Oliveira C, Seruca R, Carneiro F. Genetics, pathology, and
clinics of familial gastric cancer. Int J Surg Pathol. 2006
Jan;14(1):21-33
600
Hereditary diffuse gastric cancer (HDGC)
Saraj O, Jankowski JA
Cisco RM, Ford JM, Norton JA. Hereditary diffuse gastric
cancer: implications of genetic testing for screening and
prophylactic surgery. Cancer. 2008 Oct 1;113(7 Suppl):1850-6
van Roy F, Berx G. The cell-cell adhesion molecule Ecadherin. Cell Mol Life Sci. 2008 Nov;65(23):3756-88
Yamada T, Leung WK, Ng EKW, Sung JJY.. Textbook of
Gastroenterology. Fifth Edition 2009 Page 1035.
Kelsen DP, Van De Velde CJH, Minsky BD.. Principles and
Practice of Gastrointestinal Oncology. Second Edition 2008,
Chapter 23, Gastric Cancer Management, Page 287.
This article should be referenced as such:
Kelsen DP, Van De Velde CJH, Minsky BD.. Principles and
Practice of Gastrointestinal Oncology. Second Edition 2008,
Chapter 23, Gastric Cancer Management, Page 269.
Saraj O, Jankowski JA. Hereditary diffuse gastric cancer
(HDGC). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(6):599-601.
Robertson EV, Jankowski JA. Genetics of gastroesophageal
cancer: paradigms, paradoxes, and prognostic utility. Am J
Gastroenterol. 2008 Feb;103(2):443-9
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(6)
601