Cheesman, Edmund

Coorens, Tim H H

Douzgou, Sofia

Hardcastle, Claire L

Meyer, Stefan

Nicola, Pantelis

Penn, Anthony

Ramsden, Simon

Tang, Vivian

Thorbinson, Colin

Waller, Sarah

The University of Manchester - Institutional Repository

Revision 2Embryonal sarcoma of the liver in a girl with Cockayne Syndrome Colin Thorbinson1,2, Anthony Penn1,2, Pantelis Nicola2,3,4,5, Claire Hardcastle2,4, Sarah Waller2,4, Simon Ramsden2,4, Tim H H Coorens6, Vivian Tang2,7, Edmund Cheesman2,8, Sofia Douzgou2,4,9,, Stefan Meyer1,2,3,51Department of Paediatric Haematology and Oncology, Royal Manchester Children’s Hospital, Manchester NHS Foundation Trust Manchester, UK 2Manchester Academic Health Science Centre3The Christie NHS Foundation Trust, Manchester, UK 4Manchester Centre for Genomic Medicine, Manchester, UK 5Division of Cancer Sciences, University of Manchester, UK6Wellcome Sanger Institute, Hinxton, UK7Department of Paediatric Radiology, and8Department of Paediatric Pathology, Royal Manchester Children’s Hospital, Manchester, UK 9Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK Word Count:	895Key Words: Cockayne Syndrome, Embryonal Sarcoma Liver, Chromosomal InstabilityNo. of Figures:  1Correspondence: Stefan Meyer MD PhD FRCPCHCancer Studies, Faculty of Biology, Medicine and HealthUniversity of Manchester c/o Paediatric and Adolescent Oncology Christie HospitalWilmslow Road Manchester M20 6XBUnited KingdomEmail: stefan.meyer@manchester.ac.ukDear Editor     Cockayne syndrome (CS) is a chromosomal instability syndrome, characterised by developmental abnormalities, motor and cognitive deficits, and sun-sensitivity. Cells from CS patients show increased ultraviolet (UV) radiation sensitivity, with impaired RNA and DNA synthesis after UV exposure1. Most cases of CS are caused by pathogenic variants in ERCC8 and ERRC6, encoding the CSA and CSB proteins 1,2. Pathogenic variants in other ERCC-family genes can also cause a CS-like phenotype, linking CS to other chromosomal instability syndromes, such as pathogenic variants in ERCC1 causing also Fanconi anaemia and Xeroderma pigmentosum. CSA and CSB are integral to Transcription-Coupled Nucleotide Excision Repair (TC-NER), and linked to other DNA repair pathways, partly via direct protein interactions3. However, in contrast to other DNA repair defective syndromes, CS was noted not to predispose to cancer4. We report a girl with written consent from the family (birth weight 3.1kg, 25th centile, OFC 31.5cm, 0.4-2nd centile) with cataracts, periventricular calcifications, and developmental delay aged 5 months (appearances Figure 1A). Investigations for associated genetic causes included NGS-panel sequencing with Sanger sequencing confirmation, and identified two pathogenic variants in ERCC6 (Figure 1B, paternal allele: c.2167C>T, r.1993_2169Del (exon 10), p.Phe665_Gln723del; maternal allele: c.2599-26A>G,  r.2598_2599ins2599-25_2599-1(partial insertion intron 13), p.Met867Thrfs*14). Both variants were previously described in CS with variable severity1, confirming CS. Aged 3 and ½ years imaging for abdominal symptoms and elevated liver enzymes revealed a heterogeneous liver mass (Figure 1C). Biopsy showed large, spindle-shaped or stellate cells set within a myxoid stroma, and cytonuclear pleomorphism with hyperchromatism, multinucleated with atypical mitotic figures, with positivity for desmin and retained INI1. The appearances (Figure 1D) were consistent with an undifferentiated embryonal sarcoma of the liver (UESL). Three months post resection with tumour at resection margins, she suffered a massive abdominal recurrence and passed away six months after the initial diagnosis of UESL. This is the first report of a malignancy in an individual affected by CS, a DNA repair disorder notable for its absence of cancer predisposition.4 This UESL, a rare disease (less than 10% of childhood liver tumours, commonly between 6-10 years5), challenges this thinking. NER-defects are not predisposing to sarcomas, and UESL has not been reported associated with any specific genetic condition. While CS and UESL might be only coinciding, the hepatic vulnerability with CS supports the hypothesis that CS and UESL might be causally linked: Elevated liver enzymes are commonly encountered in CS2, and patients can experience liver failure with metronidazole administration. The liver pathology in CS and the UESL might share aspects of their respective pathogenesis. While CS does not predispose to common NER-associated malignancies, the association of CS with UESL shows that CS-affected individuals can develop malignancies. Author Contributions: Oncology: CT, AP, SM; Genetics: PN, CH, SW, SR, TC, SD; Histology and radiology: VT, EC; all: manuscript finalisation.Acknowledgements: The authors thank the family for sharing their daughter’s story and providing photographic illustrations. Conflict of Interest:  The authors declare no conflict of interest.1.	Calmels N, Botta E, Jia N, et al. Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. J Med Genet. 2018;55(5):329-343.2.	Wilson BT, Stark Z, Sutton RE, et al. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2016;18(5):483-493.3.	Tiwari V, Baptiste BA, Okur MN, Bohr VA. Current and emerging roles of Cockayne syndrome group B (CSB) protein. Nucleic Acids Res. 2021;49(5):2418-2434.4.	Reid-Bayliss KS, Arron ST, Loeb LA, Bezrookove V, Cleaver JE. Why Cockayne syndrome patients do not get cancer despite their DNA repair deficiency. Proc Natl Acad Sci U S A. 2016;113(36):10151-10156.5.	Ismail H, Dembowska-Baginska B, Broniszczak D, et al. Treatment of undifferentiated embryonal sarcoma of the liver in children--single center experience. J Pediatr Surg. 2013;48(11):2202-2206.Figure 1: A: Face of the girl in her first year (left). Age 3 years and 8 months with growth failure when compared with 2 months old sibling (right). B: ERCC6 pathogenic variants c.2167C>T (upper panel) and c.2599-26A>G (lower panel). C: T2 (left) and T1 MR images: pedunculated mixed cystic solid liver mass, right lobe of the liver (arrows). D: Large, spindle-shaped, or stellate cells with cytonuclear pleomorphism and hyperchromatism, brisk mitotic activity and atypical mitotic figures (left, middle). Diffuse positivity for p53 (right): undifferentiated embryonal sarcoma of the liver (left and right panel ×4, scale bar 500 µm; middle ×10, scale bar 100 µm).

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Embryonal sarcoma of the liver in a girl with Cockayne Syndrome

Embryonal sarcoma of the liver in a girl with Cockayne Syndrome

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