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Hereditary Gastric Cancer – Diagnosis and Clinical Implications
1Banasiewicz
Tomasz, 2,3 Stojcev Zoran, 4Pławski Andrzej
Department of General Surgery, Oncologic Gastroenterological and Plastic Surgery, Poznań
University of Medical Sciences, Poland
2 Regional Hospital, Słupsk, Department of General, Vascular and Oncologic Surgery, Słupsk, Poland
3 Department of Oncologic Surgery, Gdańsk Medical University, Gdańsk, Poland 4 Institute of Human
Genetics, Polish Academy of Sciences Poznan, Poland
1
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited
Abstract
Gastric cancer is still one of the world's leading causes of cancer mortality. Approximately 10% of
gastric cancers appear to have a familial predisposition. In this this group, 1-3% are considered as
hereditary syndromes, with a clear genetic pathway, associated with the most important
mechanisms of the CDH1 germline mutations. This mutation leads to the hereditary diffuse gastric
cancer syndrome (HDGC). Other syndromes of familial prevalence of the gastric cancer, correlated
with genetic mutations, are the hereditary nonpolyposis colorectal cancer, Li-Fraumeni syndrome,
Peutz-Jeghers syndrome, Familial Adenomatous Polyposis, Cowden disease. Families HDGC can be
identified and tested for causative mutations in CDH1; in other syndromes screening
gastroduodenoscopy is indicated.
Key words gastric cancer; CDH1 mutations; gastrectomy, HDGC
Hereditary Gastric Cancer
3% are considered as hereditary syndromes,
with a clear genetic pathway, associated with
Gastric cancer is one of the world's leading
the most important mechanisms of the CDH1
causes of cancer mortality [1], with an average
germline mutations leaded to the hereditary
700,000 deaths a year [2, 3]. There are two
diffuse gastric cancer syndrome (HDGC). Other
main histological types, diffuse and intestinal.
syndromes, correlated with genetic mutations
Intestinal type usually follows multifocal
are the hereditary nonpolyposis colorectal
atrophic gastritis and accompanied by
cancer, Li-Fraumeni syndrome, Peutz-Jeghers
intestinal metaplasia is more frequently
syndrome, Familial Adenomatous Polyposis,
observed in older patients. Diffuse cancer,
Cowden disease, gastric adenocarcinoma and
observed more frequently on young patients,
proximal polyposis of the stomach (GAPPS) and
can be multifocal and can be hereditary [4].
others [5].
Approximately 10% of gastric cancers appear
to have a familial predisposition, and only 10%
shows a familial cluster. In this this group, 1Address for correspondence and reprint requests to:
Department
of
General
Surgery,
Oncologic
Gastroenterological and Plastic Surgery, Poznań University of
Medical Sciences, Poland Email [email protected]
© 2014 Tomasz B et al. Licensee Narain Publishers Pvt. Ltd.
(NPPL)
Submitted Friday, June 14, 2013Accepted Tuesday, August
06, 2013Published: Wednesday, Sunday, January 26, 2014
1
Gastric carcinoma involves numerous genetic
and epigenetic alterations. The most common,
sporadic gastric cancer is developed through
multistep processes, including the infectious
cases as Helicobacter pylori or Epstein-Barr
virus. Those types of the two infectionassociated gastric cancers are characterized by
global CpG island methylation in the promoter
region of cancer-related genes [6]. A
significantly smaller part of gastric cancers can
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World J Surg Med Radiat Oncol 2014;3:1-9
be caused by a specific germ-line mutation of
the E-cadherin gene (CDH1).
Germline mutations in the E-cadherin/CDH1
gene
The existence of a familial form of gastric
cancer was described in the Napoleon
Bonaparte family, with multiple cases of the
gastric cancers in this family [7]. During long
years individuals from these families lived with
the uncertainty of developing lethal gastric
cancer, but now families with this type of
gastric cancer can be identified and tested for
causative mutations in CDH1 [8]. The
cumulative lifetime risk of developing gastric
cancer in CDH1 mutation carriers is up to 80%.
Women from these families have an increased
risk for developing lobular breast cancer [9].
Approximately 1–3% of gastric cancer can be
caused by a germline mutation in the CDH1
gene, encoding E-cadherin. The data from these
families suggest that the penetrance of CDH1
gene mutations is high, ranging between 70 and
80% [10]. In families with HDGC CDH1
germline mutation is observed in 30-40%, the
remaining 60–70% are genetically unexplained
and may be caused by alterations in other
genes [11]. Those mutations were initially
identified in 1998 in New Zeeland, in Maori
families that were predisposed to diffuse
gastric cancer [12].
E-cadherin plays an import role in the
processes of development, cell differentiation,
and maintenance of epithelial architecture [13].
Analysis of genetic abnormalities in CDH1found
in HDGC shows that the most common are
inactivating mutations (splice site, frameshift,
and nonsense) rather than missense mutations.
Furthermore, CDH1 germline mutations are
evenly distributed along the E-cadherin gene. In
families with HDGC recently frequent deletions
of CDH1 have been recognized [14]. The
clustering in exons 7–9 is observed in sporadic
diffuse gastric cancer C [15].
Loss of
heterozygosity as the “second hit” does not
appear to be frequent in HDGC. As well as Ecadherin dysregulation, overexpression of
2
Tomasz B et al.
epidermal growth factor receptor (EGFR) is
among the most frequent genetic alterations
associated with diffuse-type gastric carcinoma.
There are some evidence suggests a functional
relationship between E-cadherin and EGFR that
regulates both proteins [16].
Germline alleles of E-cadherin (CDH1) can
explain approximately 30-40% of HDGC. The
factors driving susceptibility for the remaining
families remain unknown. Some of them can be
explain for example by the germline truncating
allele of alpha-E-catenin (CTNNA1). It can call
attention to the broader signaling network
surrounding these proteins in HDGC, because
alpha-E-catenin functions in the same complex
as E-cadherin [17].
Microsatellite Instability
Genetic instability at the level of microsatellite
instability (MSI) occurs in many sporadic
human cancers. The levels of MSI found in
gastric carcinomas from both Western and
Eastern populations are probably in the region
of up to 15–20% [18, 19]. In some studies
frameshift mutations in the Wnt pathway genes
AXIN2 and TCF7L2 have been found in GCs with
high microsatellite instability [20]. Alternative
lengthening of telomeres frequently occurs in
mismatch repair system-deficient gastric
carcinoma [21]. Several authors demonstrated
that the subset of sporadic GC with highfrequency MSI (MSI-H) is characterized by the
distinct clinicopathologic and genetic profile,
when compare with those with a low frequency
(MSI-L) or microsatellite stable (MSS) genotype
[22, 23, and 24]. However, whereas the role of
microsatellite instability and DNA mismatch
repair gene defects in HNPCC is unquestionable
and well established, the relevance of this
phenomenon in GC has limited clinical value
and is currently still don’t recognized [25].
Others Hereditary Syndromes
There are
risk of the
associated
mismatch
multiple syndromes with elevated
gastric cancer, as: Lynch syndrome
with germline mutations in DNA
repair genes and microsatellite
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World J Surg Med Radiat Oncol 2014;3:1-9
instability, in hereditary breast and ovarian
cancer syndrome due to germline BRCA1 and
BRCA2 mutations, in familial adenomatous
polyposis caused by germline APC mutations, in
Li-Fraumeni syndrome due to germline p53
mutations,
in
Peutz-Jeghers
syndrome
associated with germline STK11 mutations, in
juvenile polyposis syndrome associated with
germline mutations in the SMAD4 and BMPR1A
genes and in Cowden disease associated with
mutations in PTEN gene [26].
FAP: The incidence of gastric cancer in Western
FAP patients is not significantly different from
the general population.Asian patients, on the
other hand, have increased prevalence of
gastric cancer in FAP patients (2, 1 - 4.2%) [27].
In most cases gastric cancer arises from
adenomatous
polyps
via
the
adenomacarcinoma sequence, but several
reports
have
shown
that
gastric
adenocarcinoma can be developed from fundic
gland polyp in FAP patients [28,29,30].
Fundic gland polyps are the most prevalent
gastric lesions, followed by adenomatous
polyps. Those polyps occurred in about 50% of
FAP patients and are in this group the most
common type of the gastric polyps. In some
recent study the prevalence of fundic gland
polyp was about 60%, with the prevalence of
gastric adenoma as 6-14% [31]. Fundic gland
polyps are common in familial adenomatous
polyposis and attenuated familial adenomatous
polyposis and, if voluminous, may interfere
with effective endoscopic gastric cancer
surveillance. This family is believed to be the
first of its type reported with focus upon
education and genetic counseling in the setting
of a family information service [32].
Gastric adenocarcinoma and proximal
polyposis of the stomach (GAPPS) is the new,
recent describe autosomal dominant gastric
polyposis syndrome. GAPPS is a unique gastric
polyposis syndrome with a significant risk of
gastric adenocarcinoma. It is characterised by
the autosomal dominant transmission of fundic
gland polyposis, including areas of dysplasia or
intestinal-type
gastric
adenocarcinoma,
restricted to the proximal stomach, and with no
3
Hereditary Gastric Cancer
evidence of colorectal or duodenal polyposis or
other
heritable
gastrointestinal
cancer
syndromes. This syndrome was recognized in
three families from Australia, the USA and
Canada. The affected families were identified
through referral to centralised clinical genetics
centers [33].
In a nationwide epidemiologic study in Sweden
Hemminki and Jiang [34] found that the
population-attributable proportion of familial
gastric carcinoma was much lower than that
cited in the literature. Patterns of multiple
carcinomas suggested that immunologic factors
modulate susceptibility to gastric carcinoma.
The authors concluded that environmental
factors, perhaps H. pylori infections, were the
main reason for familial clustering of gastric
carcinoma.
Gastric cancer arises also from the
accumulation of genetic and epigenetic
alterations. Genetic variants of the genes IL-10,
IL-17, MUC1, MUC6, DNMT3B, SMAD4, and
SERPINE1 have been reported to modify the
risk of developing GC. Several genes have been
newly associated with gastric carcinogenesis,
both through oncogenic activation (GSK3β,
CD133, DSC2, P-Cadherin, CDH17, CD168,
CD44, metalloproteinases MMP7 and MMP11,
and a subset of miRNAs) and through tumor
suppressor gene inactivation mechanisms
(TFF1, PDX1, BCL2L10, XRCC, psiTPTE-HERV,
HAI-2, GRIK2, and RUNX3). The another
potential mechanism involved in the gastric
carcinogenesis is the inflammatory mediator
cyclooxygenase-2 (COX-2), discussed also as a
potential molecular target for therapy [35].
Lynch syndrome: The patients with colorectal
cancer and MMR gene mutations are at
increased risk of a greater range of cancers
than the recognized spectrum of Lynch
syndrome cancers, including breast, prostate
and gastric cancer. The risk for stomach cancer
is in this patients elevated compared with the
general population (SIR = 5.65, 95% CI = 2.32
to 9.69) for both sexes [36]. In patients with
Lynch syndromes the MLH1 methylation may
lead to the increased risk colorectal cancer as
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World J Surg Med Radiat Oncol 2014;3:1-9
well as stomach cancer and possibly ovarian
and liver cancer [37]. Somatic mutations of
mismatch repair (MMR) genes such as hMLH1
or hMSH2 are extremely rare in sporadic GCs,
with only one mutation found, in hMSH2 and
two cases of a germline frameshift mutation in
hMLH1 [36]. More recently, 29 sporadic GCs
with high level of MSI were screened for
somatic mutations in MLH1, MSH2, MSH6,
MLH3, and MBD4, and only five truncating
mutations (3 in MSH6, 1 in MLH3, and 1 in
MBD4) and one missense mutation (MLH1)
were identified. All truncating mutations were
found in the coding poly-A tracts, thus
suggesting that they result from the MSI
phenotype rather than causing it [38].
However, MSI positive tumours can still lack
hMLH1 protein expression and many studies
suggest that hypermethylation of the hMLH1
promoter region may be the principal
mechanism of gene inactivation in sporadic
gastric carcinomas with a high frequency of MSI
[39,40]. There is well-known fact that MSI may
be found in sporadic carcinomas that are
characteristic of hereditary nonpolyposis
colorectal cancer (HNPCC) [41], a syndrome
where germline mutations of the mismatch
repair genes are present. Genome-wide
expression profiles of sporadic GCs with and
without microsatellite instability reveal that the
immune and apoptotic gene networks
efficiently discriminated these two cancer types
[42].
Li-Fraumeni syndrome: hereditary, as well as
sporadic, gastric cancer can also be caused by
germline mutations of the TP53tumour
suppressor gene. This mutation occurs in the
Li–Fraumeni syndrome [43] and new germ line
mutations in this gene continue to be
discovered [44]. Mutations of tumor protein
p53 (TP53) and β-catenin (CTNNB1) genes are
detected early in the development of GC.
Furthermore, significant numbers of GCs show
loss of Runx3 due to hemizygous deletion and
hypermethylation of the promoter region.
Aberrant Cdx2 expression has been shown in
precancerous lesions as well as GC. However, it
4
Tomasz B et al.
remains unclear whether Cdx2 plays an
oncogenic role in gastric carcinogenesis [45].
BRCA1 and BRCA2 gene mutations: Those
mutations increased the risk of the breast
cancer, but the risk of gastric, ovarian,
pancreatic, and prostate cancers is also higher
than in normal population [46].
Clinical implications in
hereditary gastric cancer
families
with
The recent advances in the molecular genetics
lead to the recognition of the hereditary diffuse
gastric cancer that inherited in a dominant
autosomal manner with incomplete penetrance.
About 25-30% of families fulfilling the criteria
have germline mutation of the CDH1 gene
coding the calcium-dependent E-cadherin
protein. In the families with the occurrence of
the HDGC testing for CDH1 mutation is
recommended [47,48]. HDGC families can be
identified, tested for causative mutations in
CDH1, and for those families where a
pathogenic mutation can be identified,
prophylactic total gastrectomy can be
implemented in asymptomatic mutation
carriers who elect to virtually eliminate their
risk of developing this lethal disease [49].
Prophylactic gastrectomies are recommended
in unaffected CDH1 mutation carriers, because
screening endoscopic examinations and blind
biopsies have proven inadequate for
surveillance [50] The total gastrectomy is
suggested in the early adolescent age [51]. In
families with HDGC there is also an increased
frequency of cancers occurring at other sites
such as the breast, colorectum, and prostate in
these mutation carriers [52]. However,
inclusion of associated cancers into the
definition of HDGC is not yet recommended
[53].
There is a lack of recommendation in the other
genetic syndromes with the increased risk of
the gastric cancer. In families with polyposis
syndromes esophagogastroduodenoscopy by
age 25 years or prior to colon surgery is
recommended [54]. Endoscopy should be
repeated every 1-2 years. The screening
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World J Surg Med Radiat Oncol 2014;3:1-9
esophagogastroduodenoscopy should be the
most accepted procedure in families with the
aggregation of the gastric cancers.
Prevention and Treatment in Hereditary
Gastric Cancer
Hereditary Gastric Cancer
The interesting data analyzed the influence of
the selenium on the chromosome breakage in
BRCA1 carriers suggest that this treatment may
be effective also in other genetic syndromes
correlated with the hereditary gastric cancer
[62].
The prevalence of the gastric cancer, both
sporadic as the hereditary forms, is possible
mainly through the elimination of the life style
and environmental risk factors. The cigarette
smoking and H. pylori infection are classically
associated with gastric cancer [55], and diet is a
known etiological factor, especially for
intestinal-type adenocarcinoma whereby an
adequate intake of fruit and vegetables appears
to lower the risk with ascorbic acid,
carotenoids, folates and tocopherols acting as
antioxidants [56]. There are some data
suggested, that cereal fiber intake may reduce
the risk of adenocarcinoma, particularly diffuse
type [57]. The interplay of diet on genomic
stability has been recognized, by showing that
substances such as green tea can affect
methylation status of genes [58].
Conclusions
Different studies confirm the role of selenium in
carcinogenesis.
The
development
and
progression of gastric carcinoma can be
associated with decreasing levels of serum Se.
This concept is greatly supported by the
antioxidant action of Se [59]. Supplementation
of the selenium may protect against the
development of esophageal squamous cell
carcinoma (ESCC), esophageal adenocarcinoma
(EAC), and gastric cardia adenocarcinoma
(GCA) [60]
In others hereditary syndromes with familial
prevalence of the gastric cancer, as HNPCC, LiFraumeni syndrome, Peutz-Jeghers syndrome,
Familial Adenomatous Polyposis, Cowden
disease
the
screening
esophagogastroduodenoscopy should be the
most accepted procedure
The number of genetic therapies in gastric
cancer is still very limited. Targeted therapy
against GC with ERBB2 amplification recently
improved the prognosis of patients with
advanced GC. In addition, epigenetic changes in
GC could be attractive targets for cancer
treatment with modulators. A genome-wide
search has been undertaken to identify novel
methylation-silenced genes in GC, which will
help us understand the overall molecular
features of GC and further provide novel
opportunities in the treatment of GC [61].
5
Identification of the mutation and test for
causative mutation in CDH1 is indicated in
hereditary diffuse gastric cancer syndrome. For
families, where a pathogenic mutation can be
identified, prophylactic total gastrectomy can
be implemented in asymptomatic mutation
carriers who elect to eliminate their risk of
developing this lethal disease. Prophylactic
gastrectomies are recommended in unaffected
CDH1 mutation carriers, because screening
endoscopic examinations and blind biopsies
have proven inadequate for surveillance. In
families with HDGC there is also an increased
frequency of cancers occurring at other sites
such as the breast, colorectum, and prostate in
these mutation carriers.
Competing interests
The authors declare that they have no
competing interests.
Authors' contributions
TB conceived of the study, and participated in
its design and coordination and helped to draft
the manuscript.
ZS participated in the design of the publication,
review of the literature and data analysis, final
review and draft preparation
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World J Surg Med Radiat Oncol 2014;3:1-9
PK participated in the design of the publication,
review of the literature and data analysis
AP participated in the design of the publication,
review of the literature and data analysis
All authors read and approved the final
manuscript.
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