*Purpose: Hepatoblastoma (HB), a developmental liver tumor of childhood requires liver transplantation (LT) if it remains unresectable despite chemotherapy. Post-transplant relapse in up to 20% recipients can be fatal. To predict HB relapse after LT.

*Methods: DNA samples were obtained from 17 HB tumors removed at LT. Five of these tumors were from children who relapsed after LT. Four died and one is alive 12 years after surgical resection of a solitary lung metastases. DNA methylation status was determined with probes for ≈850000 CpG sites on the Infinium Methylation EPIC BeadChip Kit (Illumina) in 17 HB tumors and 8 normal control livers (donor liver).

*Results: The relapse-prone HB methylome was comprised of 110,994 differentially methylated probes (DMPs) (adjusted p <= 0.05) with at least one DMP in the promoter region for 7,786 genes. The majority were hypomethylated. Genes related to DMPs were enriched for HB, liver cancer, inflammation, PI3K-AKTsignaling and antigen receptor mediated signaling as the top pathways. Genes with DMPs included 248 consensus cancer driver genes (COSMIC, examples AXIN1, NF2, NOTCH1, TGFBR2, EGFR, ERBB3, EYS) of which CTNNB1, GLI2, KIF58, NFE2L2, PTPN13, SMARCB1 are also associated with HB, 40 additional HB driver genes (Sumazin et al., 2017 & www.mycancergenome.org), 398 tumor suppressor genes (Zhao et al, 2016), and 39 DNA repair genes (www.mdanderson.org) (e.g., CHEK1, FANCL, FANCF). A linear discriminant analysis-based classifier was developed to distinguish tumors which relapsed compared with non-relapsing tumors using methylation level for four genes, namely, Alpha Fetoprotein (AFP), Vimentin (VIM), Aldehyde Dehydrogenase 2 Family Member (ALDH2) and Ribosomal Protein L10a (RPL10A). For our dataset, the classification equation is: class if Relapse if W’X > c where c = 0.90 (X is mean-centered). The classifier achieved a cross-validation error rate of 11.77% with two samples out of 17 misclassified. With this classifier, 4 of 5 relapses and 11 of 12 non-relapses were predicted correctly for sensitivity, specificity, positive and negative predictive values of 80%, 92%, 80% and 92%, respectively.

*Conclusions: Unresectable HB tumors that led to post-transplant relapse are characterized by differentially methylated promoters in well-known cancer and HB driver, tumor suppressor and DNA repair genes. A four-gene signature comprising differentially methylated AFP, VIM, ALDH2 and RPL10A predicts post-transplant relapse with acceptable positive predictive value and needs independent validation.

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