Causal association between clonal hematopoiesis indeterminate potential and cancer: a Mendelian randomization study.

Clonal hematopoiesis of indeterminate potential (CHIP) causes the expansion of mutated hematopoietic stem cells and produces immunophenotypically altered leukocytes, which induce a tumor-promoting inflammatory condition. However, the causal effect of CHIP on cancer remains unclear. We assessed the relationship of genetically predicted CHIP with the risk of 18 cancer types involving 612,576 cases using two-sample Mendelian randomization (MR). Genetic instruments for overall and sub-types of CHIP were obtained from the a large-scale genome-wide association study using independent (r2 < 0.001) SNPs at genome-wide significance (p < 5.0 × 10-8). Summary statistics for 18 cancers were obtained from the FinnGen, MVP, PLCO study, and large consortia. Inverse-variance weighted random-effects models were used as the primary method for estimating causal effects. Findings from independent datasets were combined using the fixed-effect model and Bonferroni corrections were applied for multiple testing. We found genetic predicted overall and DNMT3A CHIP was significantly associated with an increased risk of thyroid cancer, lung cancer, kidney cancer, brain cancer, basal cell carcinoma, and malignant melanoma after corrections. In addition, we found the causal estimate of CHIP varied across histological sub-types of cancer. Sensitivity analyses confirmed that these findings were robust. Strong associations were found between genetic predicted CHIP and an increased risk of a broad range of cancers, highlighting the importance of timely screening for CHIP in cancer early detection and prevention.