Immunogenetics of Gastrointestinal Cancers: A Systematic Review of Inborn Errors of Immunity in Humans

Background/Aims The immune system plays a key role in cancer surveillance and modulation of the tumor microenvironment. Humans with inborn errors of immunity (IEI), or primary immunodeficiencies, may be prone to recurrent mucosal bacterial and viral infections and chronic inflammation, associated with intrinsic or secondary epithelium dysfunction, a potential risk factor for early-onset gastrointestinal (GI) cancer. Methods We systematically reviewed all cases with clinical diagnoses of both an IEI and a GI cancer in three databases (MEDLINE, SCOPUS, EMBASE). In total, 76 publications satisfying our inclusion criteria were identified, and data for 149 cases were analyzed. Results Of the 149 patients with IEIs, 95 presented with gastric cancer, 13 with small bowel cancer, 35 with colorectal cancer, and six with unspecified cancer or cancer at another site. Gastric and colonic adenocarcinoma was the most common. For both gastric and colorectal cancer, age at onset was significantly earlier in patients with IEIs than in the general population, based on the SEER database. Common variable immune deficiency (CVID) was the most common IEI associated with gastrointestinal cancer. About 12% of patients had molecular genetic diagnoses, the three most frequently implicated genes being ATM, CARMIL2, CTLA4 . Impaired humoral immunity and Epstein-Barr virus (EBV) infection were frequently reported as the factors potentially underlying early-onset GI malignancy in patients with IEIs. Conclusion Patients with IEIs should be considered at risk of early-onset GI cancers, and should therefore undergo cancer screening at an earlier age. Surveillance guidance based on stratifications for genetic risk should be revised to take into account the immunogenetic contribution to GI cancers.