Molecular features of hepatoblastoma

The frequency of variants in hepatoblastoma, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[1-4] A pediatric pan-cancer genomics study found that hepatoblastoma had the lowest gene variant rate among all childhood cancers studied.[5]

Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating variants/deletions involving exon 3. CTNNB1 variants have been reported in more than 80% of cases.[1,3,4,6,7] A less common cause of WNT pathway activation in hepatoblastoma is variants in APC associated with familial adenomatosis polyposis coli.[6]

NFE2L2 variants were identified in 10 of 174 (6%), 4 of 88 (5%), and 5 of 112 (4%) cases of hepatoblastoma in three studies.[3,4,7] The presence of NFE2L2 variants was associated with a lower survival rate.[7]

Similar NFE2L2 variants have been found in many types of cancer, including hepatocellular carcinoma. These variants render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.

TERT and TP53 variants, which are common in adults with hepatocellular carcinoma,[8] are uncommon in children with hepatoblastoma.[1,3,4,6] Pediatric patients with TERT variants present with hepatoblastoma at a significantly older age, compared with patients without TERT variants (median age at diagnosis, approximately 10 years vs. 1.4 years).[7]

Uniparental disomy at 11p15.5 with loss of the maternal allele was reported in 6 of 15 cases of hepatoblastoma.[9] This finding has been confirmed in genomic characterization studies, in which 30% to 40% of cases showed allelic imbalance at the 11p15 locus.[4,6,7]

A 16-gene expression signature divided hepatoblastoma cases into two subsets,[7,10] C1 and C2. The C1 subtype included most of the well-differentiated fetal (pure fetal) histology cases. The C2 subtype showed a more immature pattern and was associated with higher rates of metastatic disease at diagnosis. In a study of 174 patients with hepatoblastoma, the C2 subtype was a significant predictor of poor outcome in multivariable analysis.[7]

A second research group also found that gene expression profiling could be used to identify subsets of hepatoblastoma with favorable versus unfavorable prognosis.[3] The unfavorable prognosis group of patients showed elevated expression of genes associated with embryonic stem cell and progenitor cells (e.g., LIN28B, SALL4, and HMGA2). The favorable prognosis group of patients showed elevated expression of genes associated with liver differentiation (e.g., HNF1A).

A gene expression signature at chromosome 14q32 (e.g., DLK1) was identified, with a stronger expression signal being associated with higher risk of treatment failure.[4] A strong 14q32 expression signature was also observed in fetal liver tissue, further supporting the concept that patients with hepatoblastoma who have tumors with biological characteristics that are similar to those of hepatic precursor cells have an inferior prognosis.

Epigenetic profiling of hepatoblastoma has been used to identify molecularly defined hepatoblastoma subtypes. Tumors from 113 patients with hepatoblastoma were evaluated using DNA methylation arrays. Two distinctive subtypes were identified, epigenetic cluster A and B (Epi-CA and Epi-CB).[4] The methylation profile of Epi-CB resembled that of early embryonal/fetal phases of liver development. The methylation profile of Epi-CA was similar to that of late fetal or postnatal liver phases. Event-free survival was significantly lower for patients with the Epi-CB subtype than for those with the Epi-CA subtype.[4]