Impact of clonal hematopoiesis of indeterminate potential on hepatocellular carcinoma in individuals with steatotic liver disease

Introduction Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in hematopoietic stem cells with a variant allele frequency (VAF) ≥2% in genes involved in hematologic cancers, has been linked to MASLD and severe liver disease. Aim to examine whether CHIP is associated with MASLD-related HCC and its major clinical determinants. Methods patients with MASLD-related HCC (n=179), patients with advanced fibrosis without HCC (n=263), individuals with simple SLD (n=38) and healthy individuals (n=50) were enrolled. Age, sex, presence of type 2 diabetes (T2D), advanced liver fibrosis, AST and ALT levels were available.DNA was sequenced by the HiSeq 4000/NextSeq2000 platforms (Illumina). Somatic mutations were identified accepting a minimum variant coverage of 20, a minimum alternative allele count of 3 and a VAF between 0.02 and 0.46. Only somatic and variants associated to malignancy or CHIP were included. Results CHIP-defining lesions were identified in 92 out of 530 participants (17.3%).CHIP was found in 43 (24.0%) patients with HCC, 41 (15.6%) with advanced fibrosis without HCC, and in 8 (9.1%) without advanced fibrosis (p=0.006).CHIP prevalence was age-dependent, with a spike after the age of 65.The most frequently mutated gene was DNMT3A, followed by TET2, TP53 and ASXL1 (Figure 1).CHIP was associated to HCC independently of sex, diabetes, polygenic risk score of SLD and cirrhosis (OR 1.81, 95%CI 1.10-2.98; p=0.018) but association was lost when correcting for age.TET2 mutations were enriched in HCC and the association between HCC and TET2 remained significant when correcting for age, gender, diabetes, polygenic risk of SLD and cirrhosis (OR 4.35, 95%CI 1.18-16.01; p=0.029). Conclusion we suggest a possible role of CHIP in the progression of SLD and TET2 mutations showed the strongest enrichment in HCC. Further studies are needed to clarify how CHIP can contribute to hepatic carcinogenesis.