Molecular evolution of mosaic chromosome 18 copy-number alterations from gametes to hepatoblastoma

Constitutive chromosomal abnormalities often underlie developmental defects, while somatic copy-number alterations are recurrent events in cancers. Although these processes are usually studied separately, they may occasionally converge, as illustrated by the increased incidence of hepatoblastoma in children with trisomy 18. Mosaic chromosomal abnormalities, present in only a fraction of cells, offer a unique biological context to explore how developmental defects and tumorigenesis can coexist within the same individual.

We employed an integrated genomic approach, combining fluorescent in situ hybridization (FISH), whole genome sequencing (WGS), and single-nucleus RNAsequencing (snRNAseq) to characterize molecular alterations in a female patient presenting with multiple developmental delays and hepatoblastoma diagnosed at age two.

We identified a mosaic supernumerary derivative chromosome 18, karyotypically described as 47,XX,+der(18), in 10% of the patient's liver and blood cells and in 100% of tumor cells. Integrated WGS and FISH analyses revealed that the der(18) resulted from complex chromosomal rearrangements involving eight breakpoints spanning 18p11.32 to 18q12.1. Haplotype phasing indicated a pre-zygotic origin, with mosaicism resulting from early embryonic rescue via loss of the der(18). SnRNAseq of liver and hepatoblastoma tissues enabled reconstruction of copy-number evolution across development and tumorigenesis and supported the prioritization of a restricted set of dosage-sensitive chromosome 18 candidate genes recurrently deregulated in hepatoblastoma. The patient has remained recurrence-free for 32 months following surgical resection and chemotherapy.

This case reconstructs the molecular evolution of chromosome 18 alterations from the zygote to tumor formation and highlights how mosaic chromosome abnormalities can intersect with developmental defects and pediatric liver cancer.

This case study illustrates how a single chromosomal abnormality can influence both human development and cancer formation. By combining genomics and single-cell analyses, we traced the history of a rare chromosome 18 rearrangement from its origin before fertilization to its role in hepatoblastoma, a childhood liver cancer. We found that this abnormal chromosome was present in only a small fraction of normal liver and blood cells, but in all tumor cells, indicating that the cancer arose from one of these mosaic cells. Integrating single-cell and transcriptomic data enabled the prioritization of a restricted set of chromosome 18 candidate genes. This work provides a detailed example of how complex chromosomal alterations can emerge early in life, be selectively lost during development, and still leave a small population of abnormal cells that may later give rise to cancer. These findings highlight the need to consider mosaic chromosomal abnormalities as possible predisposing factors even in patients without obvious genetic syndromes, and they show the value of combining cytogenetic, genomic, and single-cell approaches to understand how cancer can develop from early developmental events.