Clonal hematopoiesis of indeterminate potential- a potential risk factor for GI malignancies Free

Introduction

Clonal hematopoiesis of indeterminate potential (CHIP) occurs when a hematopoietic stem cell undergoes clonal proliferation as a part of normal aging. Commonly involved genes include DNMT3A, TET2, ASXL1, and JAK2 and rarely, KRAS, PIK3CAand EGFR. Most people are asymptomatic, but it can seldom lead to myelodysplastic syndrome and acute myeloid leukemia. More commonly, these disorders lead to a proinflammatory state, increasing the risk of cardiovascular disease at similar rates as metabolic risk factors. In recent years, the association with non-hematological malignancies, especially gastrointestinal cancers, has been studied. In the review, we have summarized the association of GI malignancies with CHIP and the mutations that increase such risk.

Methods

Among patients with CHIP (P), the risk of gastrointestinal malignancy (O) compared to individuals without CH (C), based on observational studies (E) was studied. PubMed, Scopus, Google Scholar, Embase, Cochrane Library, Web of Science, and Crossref were explored for observational studies exploring the association. After excluding duplicates, case reports, and animal studies, 7 studies were selected. From the seven studies, only 5 exclusively focused on gastrointestinal malignancy. It included 3 case-control and 2 cohort studies. PRISMA guidelines were followed, and the Cochrane risk of bias tool was then used for the selected studies, indicating heterogeneity due to different study types.

Results

The combined prevalence of CHIP in GI malignancies, including HCC, CRC, and pancreatic adenocarcinoma across the cohort studies, is approximately 19.7%. The pooled odds ratio of CHIP is approximately 1.24, with a 95% confidence interval of 1.11 to 1.39, suggesting a modest but statistically significant relationship. TET2 showed a consistently elevated risk across CRC and HCC. ATM had a strong association with CRC. ASXL1 and DNMT3A were associated with gastric cancer, with odds of around 2. Females and older individuals were at a higher risk.

Discussion

The possible correlation between CHIP and gastrointestinal cancer is a proinflammatory state and an impaired T cell function. TET2 mutation in macrophage and DNMT3 mutation in mast cells induce IL-6, IL-8, and TNF-alpha activity. This has been associated with inflammation in the gut lining, H. pylori, and elevation in transaminases with fibrosis. These have been risk factors in GI malignancies, hence indicating an indirect causation. However, the incidence is higher in older individuals. Age might be a confounding factor since CHIP and malignancies both occur in the older population, and a higher incidence amongst that group reflects the same.

Conclusion

CHIP has been associated with GI malignancies in previous studies and our review. Causation has been implicated by a pro-inflammatory state and indirect risks. However, limitations, including confounding with age, need to be explored. Currently, no guidelines exist to test for CHIP or early surveillance in people with CHIP for GI malignancies. Hence, more prospective studies with age-stratified groups need to be performed to determine the link and tailor future actions accordingly.