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. 2024 Oct 1;80(4):816-827.
doi: 10.1097/HEP.0000000000000839. Epub 2024 Mar 11.

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

Alfredo Marchetti  1   2 , Serena Pelusi  3 , Alessio Marella  1 , Francesco Malvestiti  4 , Antony Ricchiuti  1   2 , Luisa Ronzoni  3 , Marta Lionetti  2 , Vittoria Moretti  3 , Elisabetta Bugianesi  5 , Luca Miele  6   7 , Umberto Vespasiani-Gentilucci  8 , Paola Dongiovanni  9 , Alessandro Federico  10 , Giorgio Soardo  11 , Roberta D'Ambrosio  12 , Misti V McCain  13 , Helen L Reeves  13 , Vincenzo La Mura  4   14 , Daniele Prati  3 , Niccolò Bolli  1   2 , Luca Valenti  3   4   15 ; EPIDEMIC Study Investigators
Collaborators, Affiliations

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

Alfredo Marchetti et al. Hepatology. .

Abstract

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of HCC. Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD.

Approach and results: We considered individuals with MASLD-HCC (n=208) and controls with (n =414) and without (n =259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with variant allele frequency ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 , and ASXL1 , and correlated with age ( p <0.0001) and advanced liver fibrosis (p=0.001). Higher aspartate aminotransferase levels predicted non- DNMT3A -CHIP, in particular with variant allele frequency ≥10% (OR: 1.14, 1.03 -1.28 and OR: 1.30, 1.12 -1.49, respectively, p <0.05). After adjustment for sex, diabetes, and a polygenic risk, a score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30 -3.15, p =0.02), and with HCC even after further adjustment for cirrhosis (OR: 1.81, 1.11 -2.00, 1.30 -3.15, p =0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non- DNTM3A -CHIP, and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR: 2.45, 1.35 -4.53; OR: 4.8, 1.60 -17.0, p =0.02).

Conclusions: We observed an independent association between CHIP, particularly related to non- DNTM3A and TET2 genetic lesions and MASLD-HCC.

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Conflict of interest statement

Roberta D’Ambrosio consults and is on the speakers’ bureau for AbbVie and Gilead. Helen L. Reeves advises Bayer, Boston Scientific, and Eisai. She received grants from AstraZeneca. Vincenzo La Mura consults for AlfaSigma, Biomarin, CSL Behring, and Pfizer. He is on the speakers’ bureau for Gore. He received grants from Sanofi and Takeda. Daniele Prati consults, advises, is on the speaker’s bureau, and received grants from Macropharma. He consults, is on the speaker’s bureau, and received grants from Diamed, Diatech, Grifols, Immucor, Ortho Clinical Diagnostics, and Terumo. He is on the speakers’ bureau for Diasorin. Niccolò Bolli consults and is on the speakers’ bureau for Janssen. He consults for Pfizer. He is on the speakers’ bureau for Amgen and Jazz. Luca Valenti consults is on the speakers’ bureau, and received grants from Gilead. He consults for AstraZeneca, Boehringer Ingelheim, Diatech, Intercept, Ionis, Novo Nordisk, Pfizer, and Resalis. He is on the speakers’ bureau for AbbVie, AlfaSigma, and MSD. The remaining authors have no conflicts to report.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Clonal hematopoiesis of indeterminate potential (CHIP) prevalence as a function of age (p<0.0001). A steep expected increase is seen after 60 years of age and appears to be consistent across patient groups. The cumulative prevalence of clonal hematopoiesis of indeterminate potential in the overall study cohort settled around 13.1%. Cumulative prevalence of DNMT3A and TET2 mutations showing divergent age dependency in the HCC cohort with TET2 plateauing after 75 years of age.
FIGURE 2
FIGURE 2
Oncoplot showing clonal hematopoiesis of indeterminate potential (CHIP) defining lesions across patient cohorts. Genes are ordered according to cohort frequency. Variants are color coded according to legend. Median lesion variant allele frequency is shown in the left barplot. Bottom ribbons identify disease groups, presence or absence of cirrhosis, and HCC. Abbreviation: TMB, total mutation burden.
FIGURE 3
FIGURE 3
Violin plot displaying AST and ALT levels (log10 [IU/L]), as biomarkers of liver fat and AST of liver inflammation, respectively, between samples with detectable clonal hematopoiesis (CHIP; in the absence of DNMT3A mutations), CHIP with an allele fraction ≥10%, and nonmutated samples. Additional stratification according to cirrhotic status is shown. Statistically significant differences are marked by an asterisk (p<0.05, at generalized linear models adjusted for type 2 diabetes, body mass index, age, and sex. Abbreviations: CHIP, clonal hematopoiesis of indeterminate potential; VAF, variant allele frequency.
FIGURE 4
FIGURE 4
Forest plot displaying the association between HCC, CHIP, and CHIP subgroups multivariable at analysis, including type 2 diabetes, age at study enroll, cirrhosis, sex, and PRS-5 score as covariates. Absolute counts of patients with concomitant HCC and CHIP and HCC without CHIP are shown in the first 2 columns. OR and their 95% CI associating CHIP subtypes to HCC are shown in the third column. Rows represent different CHIP subtypes. Abbreviations: CHIP, clonal hematopoiesis of indeterminate potential; PRS-5, polygenic risk score of fatty liver disease.
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