Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors |
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Authors: | Taryn D Treger Tasnim Chagtai Robert Butcher George D Cresswell Reem Al-Saadi Jesper Brok Richard D Williams Chrissy Roberts Nicholas M Luscombe Kathy Pritchard Jones William Mifsud |
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Institution: | 2. Francis Crick Institute, London, UK;3. Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK;4. Department of Paediatric Haematology and Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark;5. UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, UK |
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Abstract: | BACKGROUND: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence. METHODS: Droplet digital polymerase chain reaction (ddPCR) was used to evaluate 21 samples from 4 patients with DAWT. For each patient, we assessed TP53 status in frozen tumor, matched germline DNA, and circulating tumor DNA (ctDNA) from plasma, serum, and urine collected throughout treatment. RESULTS: Mutant TP53 was detectable in ctDNA from plasma and serum in all patients. We did not detect variant TP53 in the same volume (200 μl) of urine. One patient displayed heterogeneity of TP53 in the tumor despite both histological sections displaying anaplasia. Concentration of ctDNA from plasma/serum taken prenephrectomy varied significantly between patients, ranging from 0.44 (0.05-0.90) to 125.25 (109.75-140.25) copies/μl. We observed variation in ctDNA throughout treatment, and in all but one patient, ctDNA levels fell significantly following nephrectomy. CONCLUSION: We demonstrate for the first time that ddPCR is an effective method for detection of mutant TP53 in ctDNA from children with DAWT even when there is intratumoral somatic heterogeneity. This should be further explored in a larger cohort of patients, as early detection of circulating variant TP53 may have significant clinical impact on future risk stratification and surveillance. |
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Keywords: | Address all correspondence to: Taryn D Treger UCL Great Ormond Street Institute of Child Health London United Kingdom or William Mifsud Department of Pathology Sidra Medicine Doha Qatar |
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