Diagnosis, follow up and clinical management of individuals identified with a TP53 pathogenic variant

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Sofia Fernandes Sofia Fragoso Bruno Filipe Sidonia Santos Teresa Duarte Sandra Bento Beatriz Mira Ana Luis Isalia Miguel Cecilia Moura Jose Carlos Marques Isabel Claro Ines Sequeira Carvalho Pedro Louro Joana Parreira Paula Rodrigues Fatima Vaz


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

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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: 19 may 2024. doi: https://doi.org/10.18103/mra.v10i7.2846.
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