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Biallelic HMBS Inactivation Defines a Homogenous Clinico-Molecular Subtype of Hepatocellular Carcinoma

ABSTRACT: Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. Here we explore HMBS alterations in a large series of 758 HCC. We identify recurrent bi-allelic HMBS inactivation, both in AIP patients acquiring a second somatic HMBS mutation and in sporadic HCC with two somatic hits. HMBS alterations are enriched in truncative 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/ÃƒÂŸ-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affect females, in absence of fibrosis and classical HCC risk factors. These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype.

PROVIDER: EGAS00001005986 | EGA |

REPOSITORIES: EGA

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Project description:Expression profiling is a well established tool for the genome-wide analysis of the transcriptional activity of human neoplasia. However, the high sensitivity of this approach combined with the well-known cellular and molecular heterogeneity of cancer often result in extremely complex and extended expression signatures of difficult functional interpretation. The majority of sporadic colorectal cancer cases are triggered by mutations in the APC tumor suppressor gene leading to constitutive activation of the Wnt/b-catenin signaling pathway and adenoma formation. Notwithstanding this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate and malignant potential. Here, we applied cross-species comparison of expression profiles of intestinal polyps derived from hereditary colorectal cancer patients carrying APC germline mutations, and from a mouse model carrying a targeted inactivating mutation in the mouse homologue Apc. This comparative approach resulted in the establishment of a conserved signature encompassing 166 genes differentially expressed between adenomas and normal intestinal mucosa in both species. Functional analysis of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/b-catenin signal transduction pathway, as expected from the selection of APC/Apc-mutant intestinal adenomas. Moreover, the conserved signature is able to resolve expression profiles from hereditary polyposis patients carrying APC germline mutations from those with bi-allelic incativation of the MYH gene. Keywords: normal versus tumor comparison; compare expression profiles from microdissected samples with distinct germline mutations (FAP vs. MAP). Here, we report the expression profiles from normal and intestinal adenomatous tissue from FAP (familial adenomatous polyposis) and MAP (MUTY-associated polyposis) patients with established APC and MUTY germline mutations. Total RNA samples were obtianed by laser capture microdissection.

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Biallelic HMBS Inactivation Defines a Homogenous Clinico-Molecular Subtype of Hepatocellular Carcinoma

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