Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma,Journal of Hepatology

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Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma
Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-05-27 , DOI: 10.1016/j.jhep.2022.05.018
Laura Molina ₁ , Junjie Zhu ₂ , Eric Trépo ₃ , Quentin Bayard ₄ , Giuliana Amaddeo ₅ , , Jean-Frédéric Blanc ₆ , Julien Calderaro ₇ , Xiaochao Ma ₂ , Jessica Zucman-Rossi ₈ , Eric Letouzé ₉

Affiliation

Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France.
Université Paris Est Créteil, INSERM, IMRB, Créteil, France; INSERM, U955, Equipe 18 "Physiopathologie et Thérapeutiques des Hépatites Virales Chroniques et des cancers liés", Créteil, France; Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Service d'Hépatologie, Créteil, France.
Department of Hepato-Gastroenterology and Digestive Oncology, CHU de Bordeaux, Haut-Lévêque Hospital, Bordeaux, Aquitaine, France; Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, Aquitaine, France; Bordeaux Research in Translational Oncology, Université Bordeaux, Bordeaux, Aquitaine, France.
Université Paris Est Créteil, INSERM, IMRB, Créteil, France; INSERM, U955, Equipe 18 "Physiopathologie et Thérapeutiques des Hépatites Virales Chroniques et des cancers liés", Créteil, France; Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Département de Pathologie, Créteil, France.
Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Paris, France; Nantes Université, Inserm UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, Nantes, France.

Background & Aims

Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear.

Methods

Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors.

Results

We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/β-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors.

Conclusions

These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype.

Lay summary

Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.

中文翻译：

双等位基因羟甲基胆烷合酶失活定义了肝细胞癌的同质临床分子亚型

背景与目标

由血红素合成途径酶 HMBS（羟甲基胆烷合成酶）的杂合种系突变引起的急性间歇性卟啉症 (AIP)具有发生肝细胞癌 (HCC) 的高风险。然而，HMBS 在肝肿瘤发生中的作用仍不清楚。

方法

在此，我们探讨了 758 例 HCC 病例（包括 4 例 AIP 患者）中的 HMBS 改变。我们量化了HMBS突变对血红素生物合成途径中间体的影响，并研究了HMBS突变肿瘤的分子和临床特征。

结果

我们确定了复发性双等位基因 HMBS 失活，无论是在 AIP 患者中获得第二个体细胞HMBS突变还是在散发性 HCC 中具有 2 个体细胞命中。HMBS改变富含截断突变，特别是在剪接区，导致转录本结构异常。双等位基因 HMBS 失活导致其毒性底物胆色素原大量积累并与CTNNB1激活突变协同作用，导致分化良好的肿瘤的发展，其具有Wnt/β-连环蛋白通路激活的转录组学特征和 DNA 甲基化特征相关到老化。在没有纤维化和经典 HCC 危险因素的情况下，HMBS 灭活的 HCC 主要影响女性。