Molecular pathways involved in hepatoblastoma tumorigenesis in trisomy 18

e22015 Background: Trisomy 18 (T18) is the second most common aneuploidy caused by additional copies of chromosome 18. It occurs at a rate of 1 in 2000-6000 live births, with current 1-year survival rates between 5-10% of live births. Meta-analysis of tumor in T18 patients revealed 67 tumors, with 44 (66%) being HB. The contribution of underlying genetic alterations to tumorigenesis is incompletely understood. There is a reversed gender ratio in children with T18 and HB as well as more favorable histology and response to treatment. These suggest an alternative molecular pathway in these cases might promote tumorigenesis. Although there is an association between trisomy 18 and hepatoblastoma, the cause of this increased incidence is unknown. We hypothesize that SMAD4/TGFβ signaling in conjunction with canonical Wnt signaling has a role in T18 HB tumor development as well as a more fetal tumor histology. Methods: Seven patients with T18 were treated at CCHMC for HB. Five patient samples were collected at time of surgery for evaluation. Patient samples and data were collected with informed consent and institutional IRB approval. We performed transcriptomic analysis using RNA bulk sequencing data for five paired background and tumor samples. Further gene and protein expression were evaluated and compared to non-syndromic patients with HB. Histologic evaluation for tumor subtype and target proteins was performed. Results: Of the seven patients evaluated, six (85.7%) were female with a median age of diagnosis of 9 months. All patients underwent hepatectomy, with final pathology demonstrating predominantly fetal histology. All patients are currently in remission. Bulk RNAseq demonstrated upregulation of SMAD4 and TGFβ, as well as upregulation of canonical Wnt signaling pathway including Wnt3 and transcription factors Lef1, TCF4, and APC in tumor of T18 patients compared to background and non-syndromic HB patients. β-catenin immunostaining demonstrates increased or stabilized expression in tumor compared to background liver consistent with non-syndromic HB. Conclusions: We have identified a novel tumorigenic mechanism of HB in T18. Upregulation of SMAD4 in T18 results in increased TGFβ signaling, with potential crosstalk between SMAD4/TGFβ and Wnt/β-catenin signaling promoting cancer development. Further evaluation is required to understand the pathway crosstalk and impact of genetic mutation on pathway regulation.