Genotypic Characteristics of Hepatoblastoma as Detected by Next Generation Sequencing and Their Correlation With Clinical Efficacy

Abstract

BackgroundHepatoblastoma (HB) is the most common malignant embryonic liver tumor type in children under 3 years of age. In the present study, the next generation sequencing (NGS) method was used to detect the genotype characteristics of HB and summarize the correlation between the common mutation genotypes noted in this disease and the clinical treatment and prognosis. The results may aid clinical prognosis and the successful application of targeted drugs.MethodsInitially, DNA was extracted from tumor tissue specimens and peripheral blood derived from 19 pediatric patients with HB. Subsequently, DNA panel and NGS methods were used to detect tumor diagnosis and the expression levels of treatment-associated genes, followed by the summary of genotype characteristics. In addition, in order to further assess the application of immunotherapy in HB, immunohistochemical detection of programmed cell death 1 ligand 1 (PDL1) was performed in combination with tumor mutation burden (TMB) and DNA mismatch repair status analysis. Furthermore, the clinical treatment effect and prognosis of the pediatric patients were statistically analyzed according to the characteristics of the genotype. Overall prognosis and prognostic analyses in different groups were performed by Kaplan-Meier and log-rank tests, respectively. Finally, expression validation and diagnostic analysis of commonly reported genes were performed in the GSE75271 dataset, which was obtained from the Gene Expression Omnibus (GEO) database.ResultsIn the present study, certain mutated genes, including nuclear factor erythroid 2-related factor 2 (NFE2L2), catenin β1 (CTNNB1), MYCN, tumor protein p53, axis inhibition protein 1 (AXIN1) and adenomatous polyposis coli (APC) were associated with the pathogenesis of HB. During TMB and DNA mismatch repair status analyses, pediatric patients had a low TMB. All of them did not present with microsatellite instability. The immunohistochemical results indicated lower expression levels of PDL1 in HB. The complete remission (CR) rate of pediatric patients in the gene abnormality group was lower than that of the non-reported disease-associated gene abnormality group. The 2-year overall survival rate and disease-free survival rate of 19 pediatric patients with HB were 72.1% and 42.4%, respectively. Receiver operating characteristic (ROC) analysis demonstrated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and insulin growth factor 2 (IGF2) may be potential biomarkers that could be used for the diagnosis of HB.ConclusionThe genotype changes in HB were more common and the CR rate of the pediatric patients with an altered genotype was lower than that of pediatric patients without an altered genotype. In addition, pediatric patients with HB exhibited lower TMB compared with adult patients. Moreover, the data indicated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and IGF2 may be potential biomarkers that can be used for the diagnosis of HB.

Surgical Pathology Diagnostic Pitfalls of Hepatoblastoma

“…In addition, germline and somatic mutations compound developmental factors, such as low birth weight and prematurity, to influence HB induction and growth. 1,6,8,26,27 Mutations implicated in the development of HB often involve the Wnt signaling pathway, more specifically, relating to the beta-catenin protein, a transcriptional cofactor. 10,11,28 Wnt signaling is intrinsic to embryonic development, promoting organized cellular proliferation and differentiation.…”

“…In addition, germline and somatic mutations compound developmental factors, such as low birth weight and prematurity, to influence HB induction and growth. 1 , 6 , 8 , 26 , 27 …”

“… 10 , 29 It is fitting that the most frequently reported mutation in HB is in CTNNB1 , a gene encoding the beta-catenin protein, playing an important role in cell communication and adhesion. 6 , 8 , 26 AXIN1 and AXIN2 , downstream components of the Wnt pathway, contribute to beta-catenin degradation. 10 , 28 Zhang et al (2019) describe that all beta-catenin mutations are tumorigenic when co-expressed with mutant YAP ; they also provide context for the striking biological diversity of HB, by describing the influence of myriad beta-catenin mutation identities on tumor characteristics such as growth rate, metabolic profiles, and diverse histological appearance.…”

“… 28 , 31 Such genes include METTL3 , which consequently influences CTNNB1 as a downstream target, alongside its heterodimer partner METTL14 . 6 , 26 , 28 While the sea of genetic aberrations associated with HB can be overwhelming to behold, the pathologist is urged to remain aware of new discoveries, which are frequent. The focus of research is often the prediction of tumor behavior, tumor response to current therapies and identification of novel therapeutic targets, all of which have a tangible impact on patients.…”

“…Further categorization is described according to molecular features, as advances in immunohistochemical techniques allow the discrimination of morphologically similar tumors. 6 While the majority arise sporadically, up to a third of HB cases are associated with a genetic syndrome or congenital anomaly. 7 Among those most often implicated are Beckwith-Wiedemann syndrome, familial adenomatous polyposis, Edward syndrome (trisomy 18) and Down syndrome (trisomy 21).…”