Helicobacter pylori Infection and Gastric Adenocarcinoma
image of the cancerous process. No detectable healing effect was observed for the first three years of infection-free time, and at six years, the healing effect was modest.48
Our findings indicate that
regression of the precancerous lesions is more complete in patients with less-advanced (absence of intestinal metaplasia) diagnoses at baseline than in patients with more advanced lesions, such as intestinal metaplasia and dysplasia. This healing process eventually may prevent cancer development.
In terms of the use of non-steroidal anti-inflammatory drugs (NSAIDs), results of a recent meta-analysis showed that use of aspirin or other NSAIDs was associated with a significant reduction in the risk for gastric and esophageal adenocarcinomas.49
Clinical trials using long-term use
of cyclooxygenase 2 (COX-2) inhibitors have been suspended because of cardiovascular complications. A randomized controlled study investigated the effects of long-term treatment with the COX-2 inhibitor rofecoxib in patients with gastric intestinal metaplasia after H. pylori eradication.50
The
trial was suspended after two years, and no regression of the intestinal metaplasia was observed. More recently, a clinical trial using the less cardiotoxic COX-2 inhibitor etodolac has reported to effectively reduce metachronous carcinomas in Japanese subjects after endoscopic mucosal resection of early gastric adenocarcinomas.51
It has been hypothesized that a profound acid secretion suppression promotes dissemination of H. pylori proximally to the corpus, leading to a more extensive and severe gastritis that may favor the development of atrophy and subsequently cancer.52
Carriers of the
IL1B-511T allele are higher producers of IL-1β and have an increased risk for gastric cancer.53,54
However, two meta-analyses concluded that the
risk effect is ethnicity-specific: it is seen in Caucasians but not in most Asian populations.55,56
This contrast may be explained by the relative
frequency of the high-risk allele in the population: ~35% in Caucasians and ~50% in Asians, Africans, and Hispanics. The low prevalence of this allele in the Caucasian population makes it easier to detect a significantly increased risk compared with cancer patients, with over 50% prevalence of the allele. High prevalence in other populations may indicate biological cancer susceptibility, even though it becomes harder to detect a statistically significant elevation of the relative risk.
A recent meta-analysis including 203 relevant studies (assessing 225 polymorphisms across 95 genes) found a total of 37 polymorphisms across 27 genes to be significantly associated with gastric cancer in Asians, and 12 polymorphisms across 11 genes in Caucasians.56
In Asian
populations, polymorphisms associated with gastric cancer were: IL1B+3954T, IL8-251A, IL10-592C, IL10-1082G, and IL4-590T, among others. In Caucasian populations, polymorphisms associated with increased gastric cancer risk were: IL1B-511T, ILRN-86bp-VNTR, MTHFR-667T, and TNF-308A, among others.46
Other less well-documented factors that may increase susceptibility to gastric cancer are polymorphisms in genes US GASTROENTEROLOGY & HEPATOLOGY REVIEW
Host Genetic Susceptibility Host factors modulating the outcome of the H. pylori infection have been widely explored by investigators in several countries during the last decade. Important advances include investigations of polymorphisms in genes associated with the immune response to H. pylori infection, mainly in interleukin (IL)-1B, IL1RN, TNF, and IL10. I L-1β is a proinflammatory cytokine and a potent inhibitor of gastric acid secretion.52
encoding DNA repair enzymes such as XRCC and OGG1; detoxifying enzymes such as GTSTM, GST1, NAT1, NAT2; and protective mucin glycoproteins such as MUC6 and MUC5AC.57
Hereditary gastric cancer
predisposition syndromes, usually associated with E-cadherin mutations (previously mentioned), contribute very little to the overall incidence of gastric cancer.58
Environmental Factors
Low socioeconomic status, poor home sanitation, and home crowding during childhood increase the frequency and severity of H. pylori infection and increase cancer risk. Tobacco smoking is a recognized risk factor for several types of cancer including gastric adenocarcinomas. It has been estimated that 17% of the gastric cancer cases are attributable to smoking.3,59
Dietary factors also play an important role. Excessive salt intake increases cancer risk, while adequate intake of fresh fruits and vegetables decreases the risk.60–62
In terms of salt consumption, studies
in vitro have shown that several H. pylori genes associated with virulence (including cagA) were upregulated when the bacterium was cultured in a medium with high salt concentration. As a result, increased expression of CagA was observed, leading to alteration of gastric epithelial cell morphology and function.63
Another relevant factor is the
habitat. Subjects living in low-altitude, tropical humid regions are more frequently infected with intestinal parasites, especially helminthes, which modulate the immune response against H. pylori toward a Th2 type (anti-inflammatory),64,65
and may decrease the cancer risk. By
contrast, high-altitude mountain dwellers have lower prevalence of infection with intestinal parasites and display a Th1 (pro-inflammatory) immune response which increases cancer risk.66
The Perfect Storm
It would appear that the gastric cancer risk in a given population is influenced by more than one etiologic factor. The very high cancer risk for the high-altitude Andes Mountains’ dwellers in Colombia may be related by a combination of the following etiologic forces: low socioeconomic status; high frequency of host genetic susceptibility markers; high salt intake and low consumption of fresh fruits and vegetables; highly virulent H. pylori strains—cag-positive vacA s1m1 of European ancestry; increased CagA protein expression by H. pylori induced by high salt consumption; and Th1 (pro-inflammatory) immune response against H. pylori infection, not modulated by intestinal parasites.
Cancer Screening and Prevention
In Japan, where gastric cancer is the most common cause of cancer-related deaths, mass screening programs for gastric cancer are well developed. As a result, between 45 and 70% of gastric cancers are diagnosed at an early stage (tumor limited to the mucosa or submucosa), providing five-year survival rates between 45 and 90%.13,67 One of the screening tools for detection of subjects at risk for gastric cancer is the assessment of serum levels of pepsinogens (PGs), which reflect the extension of atrophic or metaplastic changes of the gastric mucosa.68,69
Serum PGI levels lower than 70µg/l and PGI/PGII ratio lower than 3 are associated with severe atrophy of the corpus mucosa. Serum PG tests have proven to be very useful for cancer screening in populations at high risk for gastric cancer due to their low cost and minimal invasiveness. Individuals with low PG levels will then undergo gastric endoscopy and topographic mapping.
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