Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.
Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Hepatology. 2024 Oct 1;80(4):816-827. doi: 10.1097/HEP.0000000000000839. Epub 2024 Mar 11.
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.
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).
We observed an independent association between CHIP, particularly related to non- DNTM3A and TET2 genetic lesions and MASLD-HCC.
代谢相关脂肪性肝病（MASLD）是一种全球性流行疾病，是 HCC 发病率迅速上升的主要原因。不确定潜能的克隆性造血（CHIP）可导致肿瘤和心脏代谢紊乱，并被认为是组织炎症的先兆。最近，CHIP 与肝病风险增加相关。本研究旨在探讨 CHIP 是否与 SLD 患者的 HCC 发展相关。
我们考虑了 MASLD-HCC 患者（n=208）和对照组患者（n=414）和无高级纤维化患者（n=259），他们均接受了全外显子组测序。当≥2 个变异呼叫器识别出≥2%等位基因频率的已知髓系突变时，诊断为 CHIP。116 名参与者（13.1%）中观察到 CHIP，最常见的是 DNMT3A、TET2、TP53 和 ASXL1，与年龄（p<0.0001）和高级纤维化（p=0.001）相关。较高的天冬氨酸转氨酶水平预测非 DNMT3A-CHIP，特别是等位基因频率≥10%（OR：1.14，1.03-1.28 和 OR：1.30，1.12-1.49，p<0.05）。在调整性别、糖尿病和多基因风险后，遗传性 MASLD 易感性 CHIP 评分与肝硬化相关（2.00，1.30-3.15，p=0.02），即使在进一步调整肝硬化后，也与 HCC 相关（OR：1.81，1.11-2.00，p=0.002）。尽管 CHIP 的衰老和发展以及非 DNTM3A-CHIP 和 TET2 病变与 HCC 之间存在很强的共线性，但在充分校正临床/遗传协变量和年龄后，非 DNTM3A-CHIP 和 TET2 病变仍与 HCC 相关（OR：2.45，1.35-4.53；OR：4.8，1.60-17.0，p=0.02）。
我们观察到 CHIP 与 MASLD-HCC 之间存在独立的关联，特别是与非 DNTM3A 和 TET2 遗传病变相关。
