Screening for Gastric Cancer in High-risk Population
High Risk Population
First degree relatives of patients with gastric cancer have a 1.5-fold to 3-fold increased
risk of developing gastric cancer themselves (Brenner H et al, Cancer 2000;88:274-9). In
relatives of gastric cancer patients who are also carriers of a CagA positive strain of H.
pylori, the risk is 8-fold. Mucosal atrophy, hypochlorhydria, high lymphoid follicle
density, pangastritis, and interleukin 1 β polymorphism are frequent in family members of
gastric cancer patients and are associated with increased risk of the disease (El-Omar EM et
al, Gastroenterology 2000;118:22-30, Sepulveda A et al, Am J Gastroenterol 2002;97:1365-70).
Helicobacter Pylori - Carcinogen Number I
Helicobacter pylori is the main known carcinogen. The positive correlation between H. pylori
infection and development of gastric cancer is well established and proved in prospective,
controlled, studies, in Japan (Uemura N et al, N Engl J Med 2001;345:784-9, Fukase K et al,
Specific changes (mutation in oncogens, LOH of tumor suppressor genes, deletion or
insertion), different for intestinal or diffuse type gastric cancer, were described. Most of
these pre-malignant changes happened on a background of long lasting chronic inflammation,
following the cascade of atrophy, intestinal metaplasia, and dysplasia. Genetic syndromes
are rare and families clustering of gastric cancer are usually attributed to common H.
pylori infection. A family syndrome of gastric cancer due to germ-line mutation in
E-cadherin has been described, and gastric cancer may be part of Lynch syndrome (HNPCC).
Mutations and polymorphism of IL-1b and TNFa have been described in first degree relatives
of gastric cancer patients, and considered predictive factors for cancer.
Screening for Gastric Cancer
Screening for gastric cancer gained popularity in Japan, where the disease is highly
prevalent. This approach is not cost-effective in the Western word, where gastric cancer
incidence is low, but still cost-effective in high-risk population: Helicobacter pylori
infected people, first degree relatives of gastric cancer patients, patients with autoimmune
atrophic gastropathy and pernicious anemia, families with HNPCC and patients who underwent
partial gastrectomy. Since treatment for gastric cancer is not very effective and
5-year-survival is low, it is recommended to screen this population with periodic
gastroscopy and biopsies. The finding of high grade dysplasia or early gastric cancer will
enable early intervention and cure. In addition H. pylori may be diagnosed in gastric
biopsies (direct evaluation in H&E, Giemsa or Genta staining, culture, PCR or urease rapid
test), mucin secretion pattern may be assessed by immunohistochemistry with PAb's, MAb's or
lectins, JCV TAg may be demonstrated by IMH or PCR).
Mucins in the Healthy Stomach and Gastric Cancer
Normal gastric mucus expresses the mucins MUC1, MUC5AC and MUC6 (Carrato C et al,
Gastroenterology 1994;107:160-72). The development of gastric carcinoma is associated with
changes in mucin expression, namely a decrease in MUC5AC and MUC6 and aberrant de novo
expression of other MUCs (Ho SB et al, Cancer Res 1995;55:2681-90). Helicobacter pylori
infection induces a wide range of changes in the gastric mucus. There is a reversible
alteration of mucus glycosylation, which affects the protective function of the gastric
mucins (Ota H et al, Virchows Arch 1998;433:419-26).
Screening for the High-Risk Phenotype
In addition to gastroscopy and histology, which are the gold standards for screening and
prevention of gastric cancer, several other approaches, some of them are non-invasive, were
suggested. Acid hyposecretion can be measured directly or indirectly, mucin output can be
measured in gastric secretion collected by a naso-gastric tube and mucin species identified
by dot-blot for gastric mucins (MUC5AC, MUC6 and MUC1), H. pylori status can be defined with
13C-UBT, serology or stool antigen test, pepsinogen I, pepsinogen II, gastrin and B12 can be
measured in the serum. The combination of the procedures mentioned above may contribute to
an accurate characterization of the high-risk individual, suitable for invasive procedure
such as gastroscopy with biopsies.
1. To characterize the high risk individual for gastric cancer development
2. To establish a screening plan for early detection and prevention of gastric cancer in
first degree relatives of gastric cancer patients.
3. To validate new procedures for assessing risk factors for development of gastric
cancer: gastric acid output, gastric mucin output, serum levels of pepsinogen I,
pepsinogen II, gastrin B12, H. pylori status (serology, histology, urease test,
4. To assess genetic changes in the gastric mucosa of the screenees in comparison with
gastric cancer patients and controls
We will approach 50 gastric cancer patients treated in Rabin Medical Center, and ask for
their consent to approach first degree relatives for participating in the study. For each
gastric cancer patient 4 relatives will be asked to signed an informed consent and undergo
the study procedures. For each participant a matched control for age, sex and background
diseases, out of consecutive GERD patients undergoing gastroscopy, will be asked to join the
study. Thus, we will screen 200 first degree relatives of gastric cancer patients, and 200
1. First relative, man or woman, of gastric cancer patients.
2. Signed informed consent.
3. Age 18-60.
1. Severe back ground disease.
2. State after gastric surgery.
3. COPD, CHF, CRF and any disease with respiratory disturbances.
4. Deviation of the nasal septum, lack of venous access at the dorsum of the hand or any
other technical problem prevents gastric acid collection or base excess evaluation.
This is a prospective, controlled, 4 days study. All procedures followed are in accordance
with the ethical standards of the committee on human experimentation of the Rabin Medical
Center, and in accordance with the Declaration of Helsinki. In the screening meeting the
participant or the control will be told about the aims and nature of the study, and will be
comprehensively informed about all procedures, anticipated results and risks. After agreeing
to participate they will sign the informed consent. A medical history, family history and
symptomatic questionnaire will be filled, and the participant will be scheduled for
gastroscopy. After a night fast gastroscopy will be performed, biopsies will be taken as
needed for the different protocols (see below). Then gastric acid output, mucin output and
alkaline tide studies will be performed. Blood will be drawn for "gastro panel" of BioHit,
routine blood tests, B12, CEA, CA19-9, and CAG A serology. In another day, 13CUBT and IFOBT
will be performed.
Observational Model: Cohort, Time Perspective: Prospective
Characterization of the high-rik individual for gastric cancer - "Gastric Cancer Phenotype"
Yaron Niv, MD
Israel: Ministry of Health