Diagnosis, follow up and clinical management of individuals identified with a TP53 pathogenic variant
Main Article Content
Abstract
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome. Germline pathogenic/likely pathogenic variants (P/LPVs) in the TP53 gene are the only known genetic cause of this entity. Due to the severe phenotype and controversy over increasing surveillance and risk-reducing measures, TP53 testing has traditionally only been offered when strict criteria were met. However, with the application of next generation sequencing (NGS) to multigene testing (MGT), such as hereditary breast cancer panels, TP53 variants are being increasingly detected. In our multidisciplinary program, 2389 TP53 molecular tests were performed between January 2000 and December 2021, resulting in the identification of 29 carriers harboring 20 different TP53 P/LPVs, including one not previously described [c.242del p.(Thr81Asnfs*42)] and another of variable penetrance [c.799C>T p.(Arg267Trp)]. Two molecular findings with low allele frequencies (LAF) required additional diagnostic workup. Family phenotypes fulfilled Chompret (n=14), classic (n=4), or none of any previously described clinical criteria (n=4). For all cancers registered, patients had a first cancer diagnosis earlier when harboring DNE_LOF (DNE_LOF: dominant negative_loss of function), notDNE_LOF, frameshift and splicing variants (p<0,05), in contrast with notDNE_notLOF and unclassified variants. Breast (either as first or subsequent diagnosis) and cancers other than sarcomas and CNS, were diagnosed earlier in patients with notDNE_LOF variants (p<0,05).
For a follow-up of 51,5 months (2-118,9), we registered 11 deaths, 9 new cancers (all in previous cancer survivors), and 6 relapses (50% sarcoma cases). Radiotherapy-associated cancer was observed in one new cancer diagnosis. One healthy male underwent preimplantation genetic testing. With this study, we reinforce the need to provide multidisciplinary programs, even for a rare patient population, to avoid clinical mismanagement.
Keywords:
Li-Fraumeni Syndrome, TP53 gene, Breast Cancer, Multigene Testing, Mosaicism, Whole-body magnetic resonance imaging
Article Details
How to Cite
FERNANDES, Sofia et al.
Diagnosis, follow up and clinical management of individuals identified with a TP53 pathogenic variant.
Medical Research Archives, [S.l.], v. 10, n. 7, july 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2846>. Date accessed: 24 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i7.2846.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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6 - Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989;342(6250):705-708. doi:10.1038/342705a0
7 - de Andrade KC, Frone MN, Wegman-Ostrosky T, et al. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis. Hum Mutat. 2019;40(1):97-105. doi:10.1002/humu.23673
8 - Achatz MI, Zambetti GP. The Inherited p53 Mutation in the Brazilian Population. Cold Spring Harb Perspect Med. 2016;6(12):a026195. Published 2016 Dec 1. doi:10.1101/cshperspect.a026195
9 - Bougeard G, Brugières L, Chompret A, et al. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene. 2003;22(6):840-846. doi:10.1038/sj.onc.1206155
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11 - Varley JM, McGown G, Thorncroft M, et al. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65(4):995-1006. doi:10.1086/302575
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21 - Rana HQ, Clifford J, Hoang L, et al. Genotype-phenotype associations among panel-based TP53+ subjects. Genet Med. 2019;21(11):2478-2484. doi:10.1038/s41436-019-0541-y
22 - Fortuno C, Pesaran T, Mester J, et al. Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing. Cancer Genet. 2020;248-249:11-17. doi:10.1016/j.cancergen.2020.09.002
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24 - de Andrade KC, Khincha PP, Hatton JN, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol. 2021;22(12):1787-1798. doi:10.1016/S1470-2045(21)00580-5
25 - Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17(9):1295-1305. doi:10.1016/S1470-2045(16)30249-2
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28 - Ross J, Bojadzieva J, Peterson S, et al. The psychosocial effects of the Li-Fraumeni Education and Early Detection (LEAD) program on individuals with Li-Fraumeni syndrome. Genet Med. 2017;19(9):1064-1070. doi:10.1038/gim.2017.8
29 - Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
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35 - Frone MN, Stewart DR, Savage SA, Khincha PP. Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome. JCO Precis Oncol. 2021;5:PO.21.00320. Published 2021 Nov 10. doi:10.1200/PO.21.00320
36 - Weitzel JN, Chao EC, Nehoray B, et al. Somatic TP53 variants frequently confound germ-line testing results. Genet Med. 2018;20(8):809-816. doi:10.1038/gim.2017.196
37 - Batalini F, Peacock EG, Stobie L, et al. Li-Fraumeni syndrome: not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis. Breast Cancer Res. 2019;21(1):107. Published 2019 Sep 18. doi:10.1186/s13058-019-1193-1
38 - https://www.genturis.eu/l=eng/About-us/Our-healthcare-providers/Instituto-Portugues-de-Oncologia-de-Lisboa-Francisco-Gentil-PT.html#searchText=IPO%20Lisbon
39 - https://www.sponcologia.pt
40 - Tallis E, Scollon S, Ritter DI, Plon SE. Evolution of germline TP53 variant classification in children with cancer [published online ahead of print, 2022 Mar 3]. Cancer Genet. 2022;264-265:29-32. doi:10.1016/j.cancergen.2022.02.011
41 - Chiang J, Chia TH, Yuen J, et al. Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care. JCO Precis Oncol. 2021;5:577-584. doi:10.1200/PO.20.00399
42 - Peacock EG, Grenon LM, Batalini F, Tung N. Challenges in Interpreting TP53 Pathogenic Variants With a Low Minor Allele Frequency in Germline Genetic Testing: A Case Report of a Patient With Mosaic Li-Fraumeni Syndrome. JCO Precis Oncol. 2020;4:91-95. doi:10.1200/PO.19.00279
43 - Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27(8):1250-1256. doi:10.1200/JCO.2008.16.6959
44 - Chompret A, Brugières L, Ronsin M, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82(12):1932-1937. doi:10.1054/bjoc.2000.1167
45 - Coffee B, Cox HC, Kidd J, et al. Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genet. 2017;211:5-8. doi:10.1016/j.cancergen.2017.01.002
46 - AlHarbi M, Mubarak N, AlMubarak L, et al. Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family. NPJ Genom Med. 2018;3:35. Published 2018 Dec 19. doi:10.1038/s41525-018-0074-3
47 - Kratz CP, Freycon C, Maxwell KN, et al. Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis. JAMA Oncol. 2021;7(12):1800-1805. doi:10.1001/jamaoncol.2021.4398
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49 - Trombetta MG, Dragun A, Mayr NA, Pierce LJ. ASTRO Radiation Therapy Summary of the ASCO-ASTRO-SSO Guideline on Management of Hereditary Breast Cancer. Pract Radiat Oncol. 2020;10(4):235-242. doi:10.1016/j.prro.2020.04.003
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2 - Eliyahu D, Raz A, Gruss P, Givol D, Oren M. Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature. 1984;312(5995):646-649. doi:10.1038/312646a0
3 - Jenkins JR, Rudge K, Currie GA. Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53. Nature. 1984;312(5995):651-654. doi:10.1038/312651a0
4 - Parada LF, Land H, Weinberg RA, Wolf D, Rotter V. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature. 1984;312(5995):649-651. doi:10.1038/312649a0
5 - Baker SJ, Fearon ER, Nigro JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989;244(4901):217-221. doi:10.1126/science.2649981
6 - Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in the p53 gene occur in diverse human tumour types. Nature. 1989;342(6250):705-708. doi:10.1038/342705a0
7 - de Andrade KC, Frone MN, Wegman-Ostrosky T, et al. Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis. Hum Mutat. 2019;40(1):97-105. doi:10.1002/humu.23673
8 - Achatz MI, Zambetti GP. The Inherited p53 Mutation in the Brazilian Population. Cold Spring Harb Perspect Med. 2016;6(12):a026195. Published 2016 Dec 1. doi:10.1101/cshperspect.a026195
9 - Bougeard G, Brugières L, Chompret A, et al. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene. 2003;22(6):840-846. doi:10.1038/sj.onc.1206155
10 - Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015;33(21):2345-2352. doi:10.1200/JCO.2014.59.5728
11 - Varley JM, McGown G, Thorncroft M, et al. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65(4):995-1006. doi:10.1086/302575
12 - Ruijs MW, Verhoef S, Rookus MA, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet. 2010;47(6):421-428. doi:10.1136/jmg.2009.073429
13 - Matzenbacher Bittar C, de Araújo Rocha YM, Vieira IA, et al. Clinical and molecular characterization of patients fulfilling Chompret criteria for Li-Fraumeni syndrome in Southern Brazil. PLoS One. 2021;16(9):e0251639. Published 2021 Sep 16. doi:10.1371/journal.pone.0251639
14 - Andrade RC, Dos Santos AC, de Aguirre Neto JC, Nevado J, Lapunzina P, Vargas FR. TP53 and CDKN1A mutation analysis in families with Li-Fraumeni and Li-Fraumeni like syndromes. Fam Cancer. 2017;16(2):243-248. doi:10.1007/s10689-016-9935-z
15 - Hu C, Hart SN, Gnanaolivu R, et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med. 2021;384(5):440-451. doi:10.1056/NEJMoa2005936
16 - Breast Cancer Association Consortium, Dorling L, Carvalho S, et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021;384(5):428-439. doi:10.1056/NEJMoa1913948
17 - Narod SA. Which Genes for Hereditary Breast Cancer?. N Engl J Med. 2021;384(5):471-473. doi:10.1056/NEJMe2035083
18 - O'Shea R, Clarke R, Berkley E, et al. Next generation sequencing is informing phenotype: a TP53 example. Fam Cancer. 2018;17(1):123-128. doi:10.1007/s10689-017-0002-1
19 - Rana HQ, Gelman R, LaDuca H, et al. Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing. J Natl Cancer Inst. 2018;110(8):863-870. doi:10.1093/jnci/djy001
20 - Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG; European Reference Network GENTURIS. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. 2020;28(10):1379-1386. doi:10.1038/s41431-020-0638-4
21 - Rana HQ, Clifford J, Hoang L, et al. Genotype-phenotype associations among panel-based TP53+ subjects. Genet Med. 2019;21(11):2478-2484. doi:10.1038/s41436-019-0541-y
22 - Fortuno C, Pesaran T, Mester J, et al. Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing. Cancer Genet. 2020;248-249:11-17. doi:10.1016/j.cancergen.2020.09.002
23 - Giacomelli AO, Yang X, Lintner RE, et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat Genet. 2018;50(10):1381-1387. doi:10.1038/s41588-018-0204-y
24 - de Andrade KC, Khincha PP, Hatton JN, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol. 2021;22(12):1787-1798. doi:10.1016/S1470-2045(21)00580-5
25 - Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016;17(9):1295-1305. doi:10.1016/S1470-2045(16)30249-2
26 - Kratz CP, Achatz MI, Brugières L, et al. Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome. Clin Cancer Res. 2017;23(11):e38-e45. doi:10.1158/1078-0432.CCR-17-0408
27 - Tak CR, Biltaji E, Kohlmann W, et al. Cost-effectiveness of early cancer surveillance for patients with Li-Fraumeni syndrome. Pediatr Blood Cancer. 2019;66(5):e27629. doi:10.1002/pbc.27629
28 - Ross J, Bojadzieva J, Peterson S, et al. The psychosocial effects of the Li-Fraumeni Education and Early Detection (LEAD) program on individuals with Li-Fraumeni syndrome. Genet Med. 2017;19(9):1064-1070. doi:10.1038/gim.2017.8
29 - Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30
30 - Khincha P, et al. Clinical and Genetic Studies of Li-Fraumeni Syndrome. ClinicalTrials.gov Identifier: NCT01443468. Title of trial. ClinicalTrials.gov identifier: NCT123456. Updated May 21, 2022. Accessed May 2, 2022. https://clinicaltrials.gov/ct2/show/study/NCT01443468
31 - Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; January 19, 1999. [updated 2019 Nov 21].
32 - National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic (Version 2.2022). http://www.nccn.org/professionals/physician_gls/genetics_bop.pdf. Accessed May 1, 2022.
33 - Masciari S, Dillon DA, Rath M, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133(3):1125-1130. doi:10.1007/s10549-012-1993-9
34 - Bakhuizen JJ, Hogervorst FB, Velthuizen ME, et al. TP53 germline mutation testing in early-onset breast cancer: findings from a nationwide cohort. Fam Cancer. 2019;18(2):273-280. doi:10.1007/s10689-018-00118-0
35 - Frone MN, Stewart DR, Savage SA, Khincha PP. Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome. JCO Precis Oncol. 2021;5:PO.21.00320. Published 2021 Nov 10. doi:10.1200/PO.21.00320
36 - Weitzel JN, Chao EC, Nehoray B, et al. Somatic TP53 variants frequently confound germ-line testing results. Genet Med. 2018;20(8):809-816. doi:10.1038/gim.2017.196
37 - Batalini F, Peacock EG, Stobie L, et al. Li-Fraumeni syndrome: not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis. Breast Cancer Res. 2019;21(1):107. Published 2019 Sep 18. doi:10.1186/s13058-019-1193-1
38 - https://www.genturis.eu/l=eng/About-us/Our-healthcare-providers/Instituto-Portugues-de-Oncologia-de-Lisboa-Francisco-Gentil-PT.html#searchText=IPO%20Lisbon
39 - https://www.sponcologia.pt
40 - Tallis E, Scollon S, Ritter DI, Plon SE. Evolution of germline TP53 variant classification in children with cancer [published online ahead of print, 2022 Mar 3]. Cancer Genet. 2022;264-265:29-32. doi:10.1016/j.cancergen.2022.02.011
41 - Chiang J, Chia TH, Yuen J, et al. Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care. JCO Precis Oncol. 2021;5:577-584. doi:10.1200/PO.20.00399
42 - Peacock EG, Grenon LM, Batalini F, Tung N. Challenges in Interpreting TP53 Pathogenic Variants With a Low Minor Allele Frequency in Germline Genetic Testing: A Case Report of a Patient With Mosaic Li-Fraumeni Syndrome. JCO Precis Oncol. 2020;4:91-95. doi:10.1200/PO.19.00279
43 - Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27(8):1250-1256. doi:10.1200/JCO.2008.16.6959
44 - Chompret A, Brugières L, Ronsin M, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82(12):1932-1937. doi:10.1054/bjoc.2000.1167
45 - Coffee B, Cox HC, Kidd J, et al. Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genet. 2017;211:5-8. doi:10.1016/j.cancergen.2017.01.002
46 - AlHarbi M, Mubarak N, AlMubarak L, et al. Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family. NPJ Genom Med. 2018;3:35. Published 2018 Dec 19. doi:10.1038/s41525-018-0074-3
47 - Kratz CP, Freycon C, Maxwell KN, et al. Analysis of the Li-Fraumeni Spectrum Based on an International Germline TP53 Variant Data Set: An International Agency for Research on Cancer TP53 Database Analysis. JAMA Oncol. 2021;7(12):1800-1805. doi:10.1001/jamaoncol.2021.4398
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