<i>Helicobacter pylori</i> infection, treatment and colorectal cancer risk by genetic predisposition: evidence from two randomised trials.

Abstract

Previous studies have suggested a possible association between <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection and an increased risk of colorectal cancer (CRC). We examined the associations of <i>H. pylori</i> infection and <i>H. pylori</i> treatment with incident CRC risk and evaluated whether these associations were modified by genetic susceptibility. This study was based on two randomised trial cohorts: the Shandong Intervention Trial (SIT; n=3365; 1995-2024) and the Mass Intervention Trial in Linqu, Shandong Province (MITS; n=180 284; 2011-2024). Within MITS, we further conducted a case-cohort study to assess CRC risk according to seropositivity for <i>H. pylori</i> virulence factors and host genetic predisposition. Compared with <i>H. pylori</i>-negative individuals, <i>H. pylori</i>-positive individuals who did not receive antibiotic treatment had a significantly higher risk of CRC (SIT: HR=2.96, 95% CI 1.30 to 6.71; MITS: HR=1.27, 95% CI 1.04 to 1.55). The increased risk was particularly evident among individuals seropositive for four <i>H. pylori</i>-specific antigens (CagA, HpaA, Omp and HP0305) and those at high genetic risk (top decile of the Polygenic Risk Score). In SIT, <i>H. pylori</i> treatment was associated with a significantly reduced CRC risk over 29.4 years of follow-up (HR=0.47, 95% CI 0.22 to 0.99), with a greater reduction observed among participants with successful eradication (HR=0.38, 95% CI 0.15 to 0.94). In MITS, no overall benefit was observed 13.8 years after treatment (HR=1.17, 95% CI 0.95 to 1.43). However, a protective effect was apparent among individuals at high genetic risk and among those seropositive for key <i>H. pylori</i>-specific antigens. In post hoc observational analyses of two established trial cohorts, <i>H. pylori</i> infection was associated with an increased risk of CRC. <i>H. pylori</i> treatment reduced CRC risk in SIT, whereas in MITS, the benefit appeared to be limited to individuals at high genetic risk or those infected with specific virulence factor subtypes.