UICC World Cancer Congress 2006

Based on extensive epidemiologic evidence, The International Agency for Research on Cancer ( WHO ) classified the infection with Helicobacter pylori as a Class I Carcinogen. The infection is acquired from family members during childhood and remains active throughout life unless treated with antibiotics. Only a small proportion of infected subjects enter the pro-neoplastic pathway. The forces that determine the neoplastic versus non-neoplastic outcome of the infection are mostly unknown. Two sets of factors are under active investigation: those related to bacterial virulence and those related to the cancer susceptibility of the host.

Two main relevant virulence genes have been identified: the cytotoxin associated or cag A gene and the vacuolating cytotoxin encoded by the vac A gene. Most strains contain the cag A gene. The CAG A protein is injected into the cytoplasm of the gastric epithelial cells by a type IV secretion apparatus. Once inside the cell, the protein is phosphorilated and induces changes which eventually may result in cell transformation. But not all CAG A proteins are equal. In Asian communities at high cancer risk the protein is more extensively phosphorilated than in Western, low risk, communities.

The vac A gene is present in all strains, but the cytotoxin is secreted only in about one half of them. The gene has two relevant domains: the signal ( s ) and the middle ( m ) domains. There is considerable polymorphism associated with those domains. The s1m1 polymorphisms are associated with bacterial virulence and increase cancer risk.

Host susceptibility factors associated with gastric cancer development have been mostly linked to pro-inflammatory cytokines. Interleukin one ( IL 1 ) beta cytokine is a strong suppressor of gastric acid secretion, an event believed to increase gastric cancer risk. The IL 1 beta -511 T polymorphism has been reported to increase gastric cancer risk in Caucasian populations. Such association does not appear to hold in Asiatic. high risk, populations.

The gastric pre-cancerous process has been characterized by a sequential series of gastric lesions: the gastritis-atrophy-metaplasia-dysplasia cascade. Since the process lasts several decades, the opportunities for prevention have been well recognized. Recently reported chemoprevention trials indicate that curing the Helicobacter pylori infection may prevent cancer development. The earlier the intervention, the greater the chances of cancer prevention. Curing the infection starts a process of healing of the gastric lesions which takes years. The cancer prevention process displays a pattern which parallels in reverse the pattern of the carcinogenic process. It follows an exponential, sigmoid shaped curve with little impact in the first two to three years, followed by a drastic improvement in the following years. The duration of the lack of exposure to the carcinogenic influences of the bacterial infection is a key event in cancer prevention. The beneficial effects of curing the infection may not be evident for several years.

Targeting subjects at high cancer risk should improve the efficacy of the prevention strategy. In a Portuguese population infection with Helicobacter pylori vac A genotype s1m1 in subjects with the IL 1 beta -511 T polymorphism carries a cancer risk 87 times greater than infection with vac A s2 in subjects with -511 C polymorphism. The challenge for cancer prevention efforts is to identify subjects with high susceptibility polymorphisms infected with highly virulent bacteria. These biomarkers may vary in different ethnic groups. High risk subjects, once identified, should enter a program of endoscopic surveillance to identify and remove dysplastic lesions and early gastric cancers.