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

Sep 22, 2026

Mosaic supernumerary derivative chromosome 18 was investigated in a female patient with multiple developmental delays and hepatoblastoma. The study combines FISH, whole genome sequencing, and single-nucleus RNA sequencing to track copy-number evolution across gametogenesis, development, and tumorigenesis. The der(18) was detected in 10% of liver and blood cells and in 100% of tumor cells, indicating a pre-zygotic origin. Integrated analyses resolve eight-breakpoint rearrangements and reconstruct cancer emergence from mosaic lineages.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Background & Aims

Methods

Results

Conclusions

Highlights

Research article Molecular evolution of mosaic chromosome 18 copy-number alterations from gametes to hepatoblastoma Authors Elise Cendres, Marianna Cornet, Zoé Gautier,…, Serge Romana, Isabelle Aerts, Theo Z. Hirsch Correspondence [serge.romana@aphp.fr](serge.romana@aphp.fr) (S. Romana), [isabelle.aerts@curie.fr](isabelle.aerts@curie.fr) (I. Aerts), [theo.hirsch@inserm.fr](theo.hirsch@inserm.fr) (T.Z. Hirsch). Graphical abstract Mosaic chromosome 18 rearrangement at the intersection of development and hepatoblastoma Case report Methods Results |
-Hepatoblastoma
-Mosaic supernumerary derivative chromosome 18 [der(18)]
-Alive with no recurrence 32 months after the end of treatment

-Pre-chemotherapy tumor biopsy and blood sample
-Post-chemotherapy surgical resection tumor sample and non-tumor liver sample | Tumor depth | 100
50
30
U MAP2
FISH

chr18 der(18) chr18 der(18) chr18 der(18)
Whole genome sequencing

0 10 20 30 40 50 60 70 80 Chromosome 18 position (Mb)
Single-nucleus RNAseq

Cell type
B cells
T cells
Myeloid cells
Fibroblasts
Cholangiocytes
Endothelial cells
Hepatocytes
Tumor cells
Complex chromosome 18 rearrangement

Full chr18
Rearranged der(18)
Evolution of chromosome 18 ploidy across
gametogenesis, development and tumorigenesis
Gametes 23,X 24,X, + der(18)

47,XX, +der(18) Zygote
Early loss ~~ ~~
of der(18)
46, XX 47,XX, +der(18)

Lineage diversification
| | --- | --- | --- | The chromosome 18 rearrangement originated before fertilization, was partially lost during development, but persisted in 100% of tumor cells Highlights: • A child with developmental defects and hepatoblastoma carried a mosaic supernumerary derivative chromosome 18. • Complex chromosome 18 rearrangement with eight breakpoints caused partial tetrasomy. • The rearrangement arose before fertilization but was partially lost during development. • Mosaic cells persisted in multiple lineages and gave rise to the tumor clone. • Multi-omics reconstruction revealed chromosome 18 evolution from zygote to cancer. Impact and implications: 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. Research article Molecular evolution of mosaic chromosome 18 copy-number alterations from gametes to hepatoblastoma Elise Cendres1 ,†, Marianna Cornet2 ,†, Zoé Gautier2 ,†, Aurore Pire2 , 3 , Noémie Urvoy2 , Guillaume Morcrette2 , 4 , Fatoumata Simaga5 , Anne Guimier6 , Christophe Chardot3 , Carmen Capito3 , Gudrun Schleiermacher7 , Julien Masliah-Planchon5 , 8 , Gaelle Pierron5 , 8 , Ilaria Taddei9 , Dominique Stoppa-Lyonnet10 , Jessica Zucman-Rossi2 , Serge Romana9 , * ,‡, Isabelle Aerts11 , * ,‡, Theo Z. Hirsch2 , * ,‡ JHEP Reports 2026. vol. 8 | 1–11 Bac

FAQs

What clinical condition is connected to mosaic chromosome 18 in this study?

The study links a mosaic supernumerary derivative chromosome 18 with developmental delays and hepatoblastoma in a childhood patient diagnosed at age two.

How did the researchers confirm the presence of the der(18) abnormality?

They used fluorescent in situ hybridization (FISH) and integrated whole genome sequencing to characterize the der(18) and quantify its presence in liver, blood, and tumor cells.

What does the study conclude about when the chromosome 18 rearrangement arose?

Haplotype phasing supports a pre-zygotic origin, with mosaicism arising from early embryonic rescue involving loss of the der(18) after fertilization.

Sep 22, 2026

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