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      Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors 1 2


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          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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          Mutant p53: one name, many proteins.

          There is now strong evidence that mutation not only abrogates p53 tumor-suppressive functions, but in some instances can also endow mutant proteins with novel activities. Such neomorphic p53 proteins are capable of dramatically altering tumor cell behavior, primarily through their interactions with other cellular proteins and regulation of cancer cell transcriptional programs. Different missense mutations in p53 may confer unique activities and thereby offer insight into the mutagenic events that drive tumor progression. Here we review mechanisms by which mutant p53 exerts its cellular effects, with a particular focus on the burgeoning mutant p53 transcriptome, and discuss the biological and clinical consequences of mutant p53 gain of function.
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            Why are there hotspot mutations in the TP53 gene in human cancers?

            The p53 gene contains homozygous mutations in ~50-60% of human cancers. About 90% of these mutations encode missense mutant proteins that span ~190 different codons localized in the DNA-binding domain of the gene and protein. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates the p53 transcriptional pathway. Eight of these mutations are localized in codons that account for ~28% of the total p53 mutations and these alleles appear to be selected for preferentially in human cancers of many tissue types. This article explores the question 'Why are there hotspot mutations in the p53 gene in human cancers?' Four possible reasons for this are considered; (1) the hotspot mutant alleles produce a protein that has a highly altered structure, (2) environmental mutagens produce allele-specific changes in the p53 gene, (3) these mutations arise at selected sites in the gene due to a specific DNA sequence, such as a methylated cytosine residue in a CpG dinucleotide, which has a higher mutation rate changing C to T nucleotides, (4) along with the observed change in mutant p53 proteins, which produce a loss of function (DNA binding and transcription), some mutant proteins have an allele-specific gain of function that promotes cancer. Evidence is presented that demonstrates the first three possibilities all contribute some property to this list of hotspot mutations. The fourth possibility remains to be tested.
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              p53 polymorphisms: cancer implications.

              The normal functioning of p53 is a potent barrier to cancer. Tumour-associated mutations in TP53, typically single nucleotide substitutions in the coding sequence, are a hallmark of most human cancers and cause dramatic defects in p53 function. By contrast, only a small fraction, if any, of the >200 naturally occurring sequence variations (single nucleotide polymorphisms, SNPs) of TP53 in human populations are expected to cause measurable perturbation of p53 function. Polymorphisms in the TP53 locus that might have cancer-related phenotypical manifestations are the subject of this Review. Polymorphic variants of other genes in the p53 pathway, such as MDM2, which might have biological consequences either individually or in combination with p53 variants are also discussed.

                Author and article information

                Transl Oncol
                Transl Oncol
                Translational Oncology
                Neoplasia Press
                29 August 2018
                December 2018
                29 August 2018
                : 11
                : 6
                : 1301-1306
                [* ]UCL Great Ormond Street Institute of Child Health, London, UK
                []Francis Crick Institute, London, UK
                []Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
                [§ ]Department of Paediatric Haematology and Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark
                []UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, UK
                [# ]Department of Paediatric Haematology and Oncology, Great Ormond Street Hospital, London, UK
                [** ]Department of Histopathology, Great Ormond Street Hospital, London, UK
                Author notes
                [* ]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. t.treger@ 123456ucl.ac.uk wmifsud@ 123456sidra.org

                Present Address: Department of Pediatrics, University of Cambridge, Cambridge, UK.


                Present Address: The Institute of Cancer Research, London, UK.


                Present Address: Department of Pathology, Sidra Medicine, Doha, Qatar.

                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                : 18 April 2018
                : 12 August 2018
                : 14 August 2018
                Original article


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