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

Abstract

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 APC, Sanger sequencing was applied for the twins, the father, and the siblings of the father. A pathogenic variant of the APC gene was identified in the father as well as the twins. The WES of the HBs in the twins identified somatic mutations, including an NRAS mutation in the tumor of the first infant (C1), and an ACVR2A 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 NRAS mutation was found in multiregional specimens of C1 and those of C2. The ACVR2A 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.