Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children’s Oncology Group
Open accessAbstract
PURPOSE: To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer. METHODS: The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively. RESULTS: Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with TP53 identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP TP53 germline variant, of which 6 (46.2%) were confirmed to be de novo. CONCLUSION: Apart from TP53, we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP TP53 variants in our sample were de novo suggests universal screening for germline TP53 P/LP variants among pediatric patients with OS should be considered.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Nearly half of pathogenic TP53 germline variants in children with osteosarcoma may be de novo.
“A practical challenge, however, is that nearly half of pathogenic TP53 germline variants in children with osteosarcoma may be de novo 121 .”
From Osteosarcoma (2022) · cites this paper as [121]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
This paper’s reference list could not be split into single entries.
Szklarczyk, D., Gable, A. L., Lyon, D., Junge, A., Wyder, S., Huerta-Cepas, J., Simonovic, M., Doncheva, N. T., Morris, J. H., Bork, P., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1131 · Cited by 17,749 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012) · Fly · doi:10.4161/fly.19695 · Cited by 11,816 · see citing works
Kumar, P., Henikoff, S., & Ng, P. C. (2009) · Nature Protocols · doi:10.1038/nprot.2009.86 · Cited by 6,521 · see citing works
THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL
Clopper, C. J., & Pearson, E. S. (1934) · Biometrika · doi:10.1093/biomet/26.4.404 · Cited by 5,106 · see citing works
ClinVar: improving access to variant interpretations and supporting evidence
Landrum, M. J., Lee, J. M., Benson, M., Brown, G. R., Chao, C., Chitipiralla, S., Gu, B., Hart, J., Hoffman, D., Jang, W., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx1153 · Cited by 4,196 · see citing works
Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms
Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. Z., Tainsky, M. A., et al. (1990) · Science · doi:10.1126/science.1978757 · Cited by 3,765 · see citing works
Self-citationSporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · cited 1× · see citing works
“It is also possible that rather than recurrence in a single gene being frequent, de novo variants recurrently affect genes in particular pathways, which is the paradigm in autism.(37) We did not identify significant enrichment among the 60 genes identified as harboring a de novo variant in phase 1 of our study.”
BackgroundCancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995
(1999) · PsycEXTRA Dataset · doi:10.1037/e407432005-001 · Cited by 1,932 · see citing works
The landscape of genomic alterations across childhood cancers
ICGC PedBrain-Seq Project, Gröbner, S. N., ICGC MMML-Seq Project, Worst, B. C., Weischenfeldt, J., Buchhalter, I., Kleinheinz, K., Rudneva, V. A., Johann, P. D., Balasubramanian, G. P., et al. (2018) · Nature · doi:10.1038/nature25480 · Cited by 1,572 · see citing works
Germline Mutations in Predisposition Genes in Pediatric Cancer
Zhang, J., Walsh, M. F., Wu, G., Edmonson, M. N., Gruber, T. A., Easton, J., Hedges, D., Ma, X., Zhou, X., Yergeau, D. A., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1508054 · Cited by 1,345 · see citing works
A cancer family syndrome in twenty-four kindreds.
Li, F. P., Fraumeni, J. F., Mulvihill, J. J., Blattner, W. A., Dreyfus, M., Tucker, M., & Miller, R. (1988) · PubMed · Cited by 1,293 · see citing works
De novo mutations in human genetic disease
Veltman, J. A., & Brunner, H. G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3241 · Cited by 845 · see citing works
Revisiting Li-Fraumeni Syndrome From <i>TP53</i> Mutation Carriers
Bougeard, G., Renaux-Petel, M., Flaman, J.-M., Charbonnier, C., Fermey, P., Belotti, M., Gauthier-Villars, M., Stoppa-Lyonnet, D., Consolino, E., Brugières, L., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.5728 · Cited by 760 · see citing works
Bouaoun, L., Sonkin, D., Ardin, M., Hollstein, M., Byrnes, G., Zavadil, J., & Olivier, M. (2016) · Human Mutation · doi:10.1002/humu.23035 · Cited by 730 · see citing works
Multiple Primary Cancers in Families With Li-Fraumeni Syndrome
Hisada, M., Garber, J. E., Li, F. P., Fung, C. Y., & Fraumeni, J. F. (1998) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/90.8.606 · Cited by 554 · see citing works
Villani, A., Shore, A., Wasserman, J. D., Stephens, D., Kim, R. H., Druker, H., Gallinger, B., Naumer, A., Kohlmann, W., Novokmet, A., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30249-2 · Cited by 546 · see citing works
Self-citationCancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome
Kratz, C. P., Achatz, M. I., Brugières, L., Frebourg, T., Garber, J. E., Greer, M.-L. C., Hansford, J. R., Janeway, K. A., Kohlmann, W. K., McGee, R., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0408 · Cited by 534 · see citing works
Self-citationMalkin, D. M. (2011) · Genes & Cancer · doi:10.1177/1947601911413466 · Cited by 507 · see citing works
Self-citationMai, P. L., Best, A. F., Peters, J. A., DeCastro, R. M., Khincha, P. P., Loud, J. T., Bremer, R. C., Rosenberg, P. S., & Savage, S. A. (2016) · Cancer · doi:10.1002/cncr.30248 · Cited by 487 · see citing works
Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families
Birch, Hartley, Tricker, Prosser, P., Condie, Kelsey, Harris, Jones, Binchy, Crowther, et al. (1994) · Cancer Research · Cited by 475 · see citing works
Mechanisms of sarcoma development
Helman, L. J., & Meltzer, P. S. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1168 · Cited by 460 · see citing works
Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.
Birch, J. M., Hartley, A. L., Tricker, K. J., Prosser, J., Condie, A., Kelsey, A. M., Harris, M., Jones, P. H. M., Binchy, A., & Crowther, D. (1994) · PubMed · Cited by 421 · see citing works
Villani, A., Tabori, U. Y., Schiffman, J. D., Shlien, A., Beyene, J., Druker, H. A., Novokmet, A., Finlay, J. L., & Malkin, D. M. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(11)70119-x · Cited by 420 · see citing works
Self-citationChompret, A., Brugières, L., Abel, A. L. V., Lemerle, J., Ronsin, M., Gardes, M., Dessarps-Freichey, F., Feunteun, J., Hua, D., Ligot, L., et al. (2000) · British Journal of Cancer · doi:10.1054/bjoc.2000.1167 · Cited by 372 · see citing works
2009 Version of the Chompret Criteria for Li Fraumeni Syndrome
Tinat, J., Bougeard, G., Baert‐Desurmont, S., Vasseur, S., Martin, C., Bouvignies, E., Caron, O., Paillerets, B. B., Berthet, P., Dugast, C., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.7967 · Cited by 348 · see citing works
Sensitivity and predictive value of criteria for p53germline mutation screening
Chompret, A., ABEL, A., Stoppa‐Lyonnet, D., Brugières, L., Pagès-Berhouet, S., Feunteun, J., & Bonaïti‐Pellié, C. (2001) · Journal of Medical Genetics · doi:10.1136/jmg.38.1.43 · Cited by 336 · see citing works
Prevalence and Spectrum of Germline Mutations of the p53 Gene among Patients with Sarcoma
Toguchida, J., Yamaguchi, T., Dayton, S. H., Beaughamp, R. L., Herrera, G. E., Ishizaki, K., Yamamuro, T., Meyers, P. A., Little, J. B., Sasaki, M. S., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199205143262001 · Cited by 305 · see citing works
Using Epidemiology and Genomics to Understand Osteosarcoma Etiology
Savage, S. A., & Mirabello, L. J. (2011) · Sarcoma · doi:10.1155/2011/548151 · Cited by 301 · see citing works
Self-citationParental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders
Campbell, I. M., Yuan, B., Robberecht, C., Pfundt, R., Szafrański, P., McEntagart, M., Nagamani, S. C. S., Erez, A., Bartnik, M., Wiśniowiecka‐Kowalnik, B., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.07.003 · Cited by 274 · see citing works
Mirabello, L., Zhu, B., Koster, R., Karlins, E., Dean, M., Yeager, M., Gianferante, M., Spector, L. G., Morton, L. M., Karyadi, D., et al. (2020) · JAMA Oncology · doi:10.1001/jamaoncol.2020.0197 · Cited by 243 · see citing works
Self-citationGermline mutations of the p53 tumor suppressor gene in children with osteosarcoma.
McIntyre, J., Smith‐Sørensen, B., Friend, S. H., Kassell, J., Børresen‐Dale, A., Yan, Y.-X., Russo, C. L., Sato, J., Barbier, N., & Miser, J. (1994) · Journal of Clinical Oncology · doi:10.1200/jco.1994.12.5.925 · Cited by 199 · see citing works
High frequency of de novo mutations in Li–Fraumeni syndrome
Gonzalez, K. D., Buzin, C. H., Noltner, K., Gu, D., Li, W., Malkin, D. M., & Sommer, S. S. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.058958 · Cited by 170 · see citing works
Self-citationGermline TP53 Variants and Susceptibility to Osteosarcoma
Mirabello, L., Yeager, M., Mai, P. L., Gastier-Foster, J. M., Gorlick, R., Khanna, C., Patiño-Garcia, A., Sierrasesúmaga, L., Lecanda, F., Andrulis, I. L., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv101 · Cited by 155 · see citing works
Self-citationTwo metachronous tumors in the radiotherapy fields of a patient with Li‐Fraumeni syndrome
Limacher, J., Frébourg, T., Natarajan‐Amé, S., & Bergerat, J. (2001) · International Journal of Cancer · doi:10.1002/ijc.1021 · Cited by 149 · see citing works
Unrevealed mosaicism in the next-generation sequencing era
Gajęcka, M. (2015) · Molecular Genetics and Genomics · doi:10.1007/s00438-015-1130-7 · Cited by 133 · see citing works
Musselman, J. R. B., Bergemann, T. L., Ross, J. A., Sklar, C. A., Silverstein, K. A. T., Langer, E. K., Savage, S. A., Nagarajan, R., Krailo, M., Malkin, D. M., et al. (2012) · PubMed Central · Cited by 27 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Beird, H. C., Bielack, S. S., Flanagan, A. M., Gill, J., Heymann, D., Janeway, K. A., Livingston, J. A., Roberts, R. D., Strauss, S. J., & Gorlick, R. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00409-y · Cited by 660 · see citing works
Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set
Kratz, C. P., Freyçon, C., Maxwell, K. N., Nichols, K. E., Schiffman, J. D., Evans, D. G., Achatz, M. I., Savage, S. A., Weitzel, J. N., Garber, J. E., et al. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.4398 · Cited by 148 · see citing works
Self-citationCancer-related Mutations with Local or Long-range Effects on an Allosteric Loop of p53
Degn, K., Beltrame, L., Hede, F. D., Sora, V., Nicolaci, V., Vabistsevits, M., Schmiegelow, K., Wadt, K., Tiberti, M., Lambrughi, M., et al. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167663 · Cited by 34 · see citing works
Clinical outcome of pediatric medulloblastoma patients with Li–Fraumeni syndrome
Kolodziejczak, A. S., Guerrini‐Rousseau, L., Masliah‐Planchon, J., Ecker, J., Selt, F., Mynarek, M., Obrecht, D., Sill, M., Autry, R. J., Stutheit-Zhao, E., et al. (2023) · Neuro-Oncology · doi:10.1093/neuonc/noad114 · Cited by 26 · see citing works
Self-citationBrown, A. L., Sok, P., Scheurer, M. E., Rabin, K. R., Marcotte, E. L., Hawkins, D. S., Spector, L. G., & Lupo, P. J. (2022) · Cancer · doi:10.1002/cncr.34248 · Cited by 14 · see citing works
Self-citationGenomic Newborn Screening for Pediatric Cancer Predisposition Syndromes: A Holistic Approach
Linga, B. G., Mohammed, S. G. A. A., Farrell, T. J., Rifai, H. A., Al-Dewik, N. I. E., & Qoronfleh, M. W. (2024) · Cancers · doi:10.3390/cancers16112017 · Cited by 12 · see citing works
Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma
Luo, M. B., Huang, M., Yang, N., Zhu, Y., Huang, P., Xu, Z., Wang, W., & Cai, L. (2023) · Bone Research · doi:10.1038/s41413-023-00265-w · Cited by 11 · see citing works
Zhang, L., Jiang, H., & Ma, H. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1548527 · Cited by 11 · see citing works
Children's Oncology Group's 2023 blueprint for research: Epidemiology
Lupo, P. J., Marcotte, E. L., Scheurer, M. E., Poynter, J. N., & Spector, L. G. (2023) · Pediatric Blood & Cancer · doi:10.1002/pbc.30566 · Cited by 7 · see citing works
Self-citationGermline De Novo Mutations as a Cause of Childhood Cancer
Rashed, W. M., Marcotte, E. L., & Spector, L. G. (2022) · JCO Precision Oncology · doi:10.1200/po.21.00505 · Cited by 7 · see citing works
Self-citationChow, E. J., Winestone, L. E., Lupo, P. J., Diller, L., Henderson, T. O., Kadan‐Lottick, N. S., Levine, J. M., Ness, K. K., Bhatia, S., & Armenian, S. H. (2022) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-22-0125 · Cited by 6 · see citing works
Fuentes-Bolanos, N., Padhye, B. D., Daley, M., Hunter, J. D., Hetherington, K., Warby, M., Courtney, E., Kirk, J., Josephi‐Taylor, S., Chen, Y., et al. (2023) · BMJ Open · doi:10.1136/bmjopen-2022-070082 · Cited by 5 · see citing works
Genetic Predisposition to Sarcoma: What Should Clinicians Know?
Vagher, J., Mehrhoff, C. J., Florou, V., & Maese, L. D. (2024) · Current Treatment Options in Oncology · doi:10.1007/s11864-024-01192-6 · Cited by 4 · see citing works
Germline predisposition to glial neoplasms in children and young adults
Das, A., Hawkins, C. E., & Tabori, U. Y. (2021) · Glioma · doi:10.4103/glioma.glioma_12_21 · Cited by 1 · see citing works
Concurrent Germline RB1 & Mosaic TP53 in a Child With Multiple Childhood Cancers
Nielsen, O. H., Stoltze, U. K., Gregersen, P. A., Hoffmann, M., Høgild, M. L., Andersen, M. K., Ahlborn, L. B., Hjalgrim, L. L., & Wadt, K. (2026) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.70256
Luckie, T. M., Scollon, S., Yu, Y., Sabo, A., Chambers, T. M., Taylor, O., Spector, L. G., Scheurer, M. E., Hawkins, D. S., Venkatramani, R., et al. (2026) · International Journal of Cancer · doi:10.1002/ijc.70705
Self-citation
- Authors
- Diessner, B. J., Pankratz, N., Hooten, A. J., Mirabello, L., Sarver, A. L., Mills, L. J., Malkin, D., Kelley, A. C., & Spector, L. G.
- Affiliations
- University of Minnesota (US)
- National Cancer Institute (US)
- University of Toronto (CA)
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN
- ORCID
- Venue
- JCO Precision Oncology
- Published
- 2020-11
- Volume
- 4
- Issue
- 4
- Pages
- 1187-1195
- ISSN
- 2473-4284 (ISSN-L)
- PMC
- PMC7608506
- OpenAlex
- W3090984898
- Cited by
- 16
- References
- 37
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 2
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- JCO Precision Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R50CA211249, U10CA180899, U10CA180886, U01CA122371)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR050938)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- osteosarcoma, TP53, germline mutations, de novo mutations, childhood cancer, germline mutation testing, case-parent trios, rare variants, hereditary cancer predisposition
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
