From the AGA Journals

Novel oncogene found in hepatoblastoma

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“Elegant work” identifies critical role

A substantial number of patients with hepatoblastoma are faced with aggressive tumors characterized by multiple nodules at diagnosis, metastases, vascular invasion, chemoresistance, and relapse. In contrast to hepatocellular carcinoma, hepatoblastoma has a low rate of genetic mutations, mainly in two genes CTNNB1 (beta-catenin) and NFE2L2/NRF2. Although only 5%-10% of patients with hepatoblastoma harbor mutations in the NFE2L2/NRF2 gene, the mutations strongly correlate with clinical features of aggressive hepatoblastoma.

Until today, the role of mutations of the NFE2L2/NRF2 gene in hepatoblastoma was unknown, which raised a question of whether the mutant NFE2L2/NRF2 is really an oncogene. This report by Dr. Wang’s group provides clear evidence that two patient-derived NFE2L2/NRF2 mutations, L30P and R34P, are critical for development of aggressive features of hepatoblastoma such as necrosis and cyst formation. Importantly, both L30P and R34P mutations significantly shortened survival of the mice, which correlates with high mortality of patients who have the NFE2L2/NRF2 mutations. It is also important that the authors found copy number variations and missense mutations in the NFE2L2/NRF2 gene by analyzing existing datasets, which emphasizes the role of NFE2L2/NRF2 mutations in aggressive hepatoblastoma.

In summary, this elegant work identified the critical role of the NFE2L2/NRF2 mutations in development of aggressive features of pediatric liver cancers such as low survival rate, fast progression of tumors, and promotion of widespread necrosis. This study also opens new directions which should address a) the combinatory effects of genetic mutations; b) the mechanisms that increase expression of the mutant oncogenes; and c) protein modifications that convert tumor suppressors into new oncogenes.

Nikolai A. Timchenko, PHD, is professor of surgery and director of the liver tumor biology program at Cincinnati Children’s Hospital Medical Center. He has no conflicts of interest, but is supported by the Internal Development Funds from CCHMC and by Fibrolamellar Cancer Foundation (FCF-0015).



A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAPS127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAPS127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAPS127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAPS127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAPS127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

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