Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups

Abstract

Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large-scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity. Conclusion: Analysis of immunohistochemical assays using antibodies targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis; our results pave the way for clinical collaborative studies to validate candidate biomarkers and test their potential to improve outcome for HB patients. (HEPATOLOGY 2017;65:104-121).H epatoblastoma (HB) is the most common pediatric liver tumor. It has an annual incidence rate of approximately 1.8 diagnosed cases per million in the United States, and this rate is increasing at more than 4.3% annually.(1) HBs are embryonal neoplasms that are most commonly diagnosed during the first 3 years of life. They are believed to arise from hepatic cell precursors and are characterized by heterogeneous histological patterns reminiscent of liver developmental stages.(2) Therapeutic strategies combining surgical resection and chemotherapy have improved outcomes for children with HB, but the prognosis for patients with advanced or chemotherapy-refractory disease remains poor.(1) In addition, the most effective platinum-based agents for treatment of HB often lead to serious long-term adverse effects, including ototoxicity and nephrotoxicity.(1)We describe the results of a comprehensive genomic analysis of the largest set of clinically annotated HBs reported to date. Such efforts have previously identified

New insights into diagnosis and therapeutic options for proliferative hepatoblastoma

“…We found that 88% of tumors were affected in β‐catenin, with 32% carrying a point mutation and 56% having exon 3 deleted. These percentages are similar to those previously reported for HB in other cohorts . Further comparisons with clinical data were limited due to the small number of samples.…”

“…A. Then, to evaluate this four‐gene signature on other cohorts, we reclustered samples from previously published transcriptomic data sets: E‐MEXP‐1851 from Cairo et al and GSE75271 from Sumazin et al Using expression of probes corresponding to HSD17B6, ITGA6, TOP2A, and VIM, we recapitulated the correct clustering for 78 out of 80 samples (97.5%) (http://onlinelibrary.wiley.com/doi/10.1002/hep.29672/suppinfo).…”

“…The 2‐year overall survival was 44% for patients with C2 tumors against 92% for patients with C1 . More recently, a genomic and transcriptomic study of 88 HBs proposed incorporating an intermediate subtype, thus dividing HBs into three groups with a distinct prognosis and unique molecular and clinical features . Both studies offered substantial insight into the genetic and transcriptional variation within HB tumors.…”

“…For example, genomic studies have pointed out the crucial role of the Wnt/β‐catenin signaling pathway in HB . Mutations in the gene encoding β‐catenin are present in approximately 80% of HBs . Furthermore, there is strong evidence for crosstalk between the Wnt/β‐catenin and Myc signaling pathways that promotes a more aggressive type of tumor and some indication that mutations in the NFE2L2 , SPOP , KLHL22 , TRPC4AP , and RNF169 genes, which are associated with the ubiquitinated protein degradation machinery, can cause childhood liver cancer beyond Wnt/β‐catenin signaling .…”

Hepatoblastoma in an 11-year-old

“…Further analyses of targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis. [14] …”