Abstract
Hepatoblastoma is a very rare embryonal liver cancer supposed to arise from the impairment of hepatocyte differentiation during embryogenesis. In this study, we investigated by exome sequencing the burden of somatic mutations in a cohort of 10 hepatoblastomas, including a congenital case. Our data disclosed a low mutational background and pointed out to a novel set of candidate genes for hepatoblastoma biology, which were shown to impact gene expression levels. Only three recurrently mutated genes were detected: CTNNB1 and two novel candidates, CX3CL1 and CEP164. A relevant finding was the identification of a recurrent mutation (A235G) in two hepatoblastomas at the CX3CL1 gene; evaluation of RNA and protein expression revealed upregulation of CX3CL1 in tumors. The analysis was replicated in two independents cohorts, substantiating that an activation of the CX3CL1/CX3CR1 pathway occurs in hepatoblastomas. In inflammatory regions of hepatoblastomas, CX3CL1/CX3CR1 were not detected in the infiltrated lymphocytes, in which they should be expressed in normal conditions, whereas necrotic regions exhibited negative labeling in tumor cells, but strongly positive infiltrated lymphocytes. Altogether, these data suggested that CX3CL1/CX3CR1 upregulation may be a common feature of hepatoblastomas, potentially related to chemotherapy response and progression. In addition, three mutational signatures were identified in hepatoblastomas, two of them with predominance of either the COSMIC signatures 1 and 6, found in all cancer types, or the COSMIC signature 29, mostly related to tobacco chewing habit; a third novel mutational signature presented an unspecific pattern with an increase of C>A mutations. Overall, we present here novel candidate genes for hepatoblastoma, with evidence that CX3CL1/CX3CR1 chemokine signaling pathway is likely involved with progression, besides reporting specific mutational signatures.
Highlights
Hepatoblastoma (HB) is the most common malignant liver tumor in the pediatric population [1], supposedly derived from hepatocyte precursors [2]
CTNNB1 somatic mutations were detected in ∼60% of the tumors here studied, including a novel pathogenic variant (A21_S33del)
Our data pointed out to a novel set of candidate genes for HB biology with a potential functional role in the HB tumorigenesis as they had an impact in the gene expression levels. This gene set was enriched among gene sets from other cancers: EGFR-KRAS-ALK–negative lung adenocarcinoma in never-smokers (CFTR, CTNNB1, EGFR, ERBB4, MXRA5, TGFBR2) [42], bladder cancer (EGFR, ERBB4, FLCN, PIK3R1, TSC2) [43], and metastatic renal cell carcinoma (DEPDC5, EGFR, FLCN, PIK3R1, TSC2) [44], suggesting they could have a broader role in cancer
Summary
Hepatoblastoma (HB) is the most common malignant liver tumor in the pediatric population [1], supposedly derived from hepatocyte precursors [2]. There is a trend toward an increasing prevalence of HBs over the last years [3]. The cause of this rising in incidence is still unknown, but a possible explanation would be the increasing survival of premature children with low birth weight, a factor associated with increased risk of HB [4]. According to the Children’s Hepatic Tumors International Collaboration (CHIC) surveys [5, 6], ∼20–30% of children with HBs have resectable tumors at the time of diagnosis. The CHIC has proposed a novel risk stratification system on the basis of prognostic features present at diagnosis [5, 6]. Five backbone groups were defined according to clinical prognostic factors—age, α-fetoprotein level (≤100 ng/mL), PRETEXT group (I, II, III, or IV), and metastasis at diagnosis
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