Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors12
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 h...
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| Published in | Translational oncology Vol. 11; no. 6; pp. 1301 - 1306 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Neoplasia Press
29.08.2018
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| Subjects | |
| Online Access | Get full text |
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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. |
|---|---|
| AbstractList | 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. |
| Author | Williams, Richard D. Roberts, Chrissy Mifsud, William Butcher, Robert Brok, Jesper Treger, Taryn D. Cresswell, George D. Chagtai, Tasnim Luscombe, Nicholas M. Al-Saadi, Reem Pritchard Jones, Kathy |
| AuthorAffiliation | Department of Paediatric Haematology and Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, UK Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK UCL Great Ormond Street Institute of Child Health, London, UK Department of Histopathology, Great Ormond Street Hospital, London, UK Francis Crick Institute, London, UK Department of Paediatric Haematology and Oncology, Great Ormond Street Hospital, London, UK |
| AuthorAffiliation_xml | – name: Department of Paediatric Haematology and Oncology, Great Ormond Street Hospital, London, UK – name: Department of Paediatric Haematology and Oncology, Rigshospitalet, Copenhagen University Hospital, Denmark – name: Francis Crick Institute, London, UK – name: Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK – name: UCL Genetics Institute, Department of Genetics, Evolution & Environment, University College London, UK – name: Department of Histopathology, Great Ormond Street Hospital, London, UK – name: UCL Great Ormond Street Institute of Child Health, London, UK |
| Author_xml | – sequence: 1 givenname: Taryn D. surname: Treger fullname: Treger, Taryn D. email: t.treger@ucl.ac.uk, t.treger@ucl.ac.uk, wmifsud@sidra.org organization: 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 – sequence: 2 givenname: Tasnim surname: Chagtai fullname: Chagtai, Tasnim organization: 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 – sequence: 3 givenname: Robert surname: Butcher fullname: Butcher, Robert organization: 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 – sequence: 4 givenname: George D. surname: Cresswell fullname: Cresswell, George D. organization: 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 – sequence: 5 givenname: Reem surname: Al-Saadi fullname: Al-Saadi, Reem organization: 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 – sequence: 6 givenname: Jesper surname: Brok fullname: Brok, Jesper organization: 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 – sequence: 7 givenname: Richard D. surname: Williams fullname: Williams, Richard D. organization: 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 – sequence: 8 givenname: Chrissy surname: Roberts fullname: Roberts, Chrissy organization: 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 – sequence: 9 givenname: Nicholas M. surname: Luscombe fullname: Luscombe, Nicholas M. organization: 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 – sequence: 10 givenname: Kathy surname: Pritchard Jones fullname: Pritchard Jones, Kathy organization: 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 – sequence: 11 givenname: William surname: Mifsud fullname: Mifsud, William email: wmifsud@sidra.org, t.treger@ucl.ac.uk, wmifsud@sidra.org organization: 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 |
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| Notes | Present Address: The Institute of Cancer Research, London, UK. Present Address: Department of Pathology, Sidra Medicine, Doha, Qatar. Present Address: Department of Pediatrics, University of Cambridge, Cambridge, UK. |
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| Snippet | 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... |
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| Title | Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors12 |
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