Double Heterozygous Pathogenic Variants in TP53 and CHEK2 in Boy with Undifferentiated Embryonal Sarcoma of the Liver

Abstract

Undifferentiated embryonal sarcoma of the liver is a rare mesenchymal malignancy that predominantly occurs in children. The relationship between this tumor entity and germline pathogenic variants (PVs) remains undefined. Here, we present the clinical case of a male patient diagnosed with undifferentiated embryonal sarcoma of the liver. Both germline and tumor samples were analyzed using next-generation sequencing. In the tumor tissue, PVs in TP53 (NM_000546.5):c.532del p.(His178Thrfs*69) and CHEK2 (NM_007194.4):c.85C>T p.(Gln29*) were identified, with both confirmed to be of germline origin. Copy number analyses indicated a loss of the wildtype TP53 allele in the tumor, consistent with a second hit, while it was the variant CHEK2 allele that was lost in the tumor. Our data indicate that the germline TP53 PV acts as a driver of tumorigenesis in the reported case and support a complex interaction between the germline TP53 and CHEK2 PVs. This case highlights the dynamic interplays of genetic alterations in tumorigenesis and emphasizes the need for continued investigation into the complex interactions between TP53 and CHEK2 PVs and into the association of undifferentiated embryonal sarcoma of the liver and Li-Fraumeni syndrome.

Keywords: CHEK2; TP53; double heterozygosity; embryonal sarcoma of the liver; synthetic lethality.

Figure 1

Hematoxylin and eosin staining of the biopsy tissue showing a myxoid and necrotic tumor with pleomorphic tumor cells, giant cells, and partial rhabdoid features that were classified as undifferentiated embryonal sarcoma of the liver (a) 12.5× magnification; (b) 400× magnification. Immunohistochemistry revealed positivity for CD56, but negativity for SMA, desmin, pancytokeratin, CD99, myogenin, MyoD1, MDM2, S100, EMA, WT1, and CD34 in the tumor cells. The Ki67 proliferation index was measured up to 40% in the sample.

Figure 2

Hematoxylin and eosin staining of the recurrent undifferentiated embryonal sarcoma of the liver at the age of 15 (a) 12.5× magnification; (b) 200× magnification.

Figure 3

MRI scans of the cervical/thoracic spine (a) and the lumbar spine/sacral bone (b–d) at the age of 18. The white arrows mark the lipomatous lesions of the vertebral bodies C7 and Th6 as well as the rounded lipomatous focus in L1 and the mass in S1–3 from which the biopsy was taken.

Figure 4

Graphical overview on the clinical course of the patient.

Figure 5

Copy number alteration and synthetic lethality interaction in tumor tissue: Loss of variant CHEK2 allele and gain of mutant TP53 allele in pediatric undifferentiated embryonal sarcoma.