Mutual Tissue Microchimerism of Hepatoblastomas in Monozygotic Twins From a Familial Adenomatous Polyposis Family

Patients with familial adenomatous polyposis (FAP) have increased risk of hepatoblastoma (HB). We report monozygotic twins with HB in a FAP family. To explore genetic alterations in the HBs of the twins, we carried out whole exome sequencing (WES), RNA-seq, and immunohistochemical analyses of the tumors. Additional multiregional digital PCR was performed to profile clonality of each tumor. To determine a pathogenic germline variant in <i>APC</i>, Sanger sequencing was applied for the twins, the father, and the siblings of the father. A pathogenic variant of the <i>APC</i> gene was identified in the father as well as the twins. The WES of the HBs in the twins identified somatic mutations, including an <i>NRAS</i> mutation in the tumor of the first infant (C1), and an <i>ACVR2A</i> mutation in the tumor of the second infant (C2). No somatic mutations were identified in the genes associated with the Wnt signaling pathway. However, accumulation of β-catenin was found in the C1 and C2 tumors by immunohistochemical staining, suggesting activation of the Wnt signaling pathway. Digital PCR analysis revealed that the <i>NRAS</i> mutation was found in multiregional specimens of C1 and those of C2. The <i>ACVR2A</i> mutation was found in multiregional specimens of C2, whereas the mutation was also identified in those of C1. The existence of a shared somatic mutation may suggest that microchimerism took place in the development of HBs through the utero-placental circulatory system. Importantly, the initiation of tumorigenesis is thought to occur during the fetal period after organ development of the liver.