Abstract
Li–Fraumeni and Li–Fraumeni like syndromes (LFS/LFL) represent rare cancer–prone conditions associated mostly with sarcomas, breast cancer, brain tumors, and adrenocortical carcinomas. TP53 germline mutations are present in up to 80 % of families with classic Li–Fraumeni syndrome, and in 20–60 % of families with Li–Fraumeni like phenotypes. The frequency of LFS/LFL families with no TP53 mutations detected suggests the involvement of other genes in the syndrome. In this study, we searched for mutations in TP53 in 39 probands from families with criteria for LFS/LFL. We also searched for mutations in the gene encoding the main mediator of p53 in cell cycle arrest, CDKN1A/p21, in all patients with no mutations in TP53. Eight probands carried germline disease-causing mutations in TP53: six missense mutations and two partial gene deletions. No mutations in CDKN1A coding region were detected. TP53 partial deletions in our cohort represented 25 % (2/8) of the mutations found, a much higher frequency than usually reported, emphasizing the need to search for TP53 rearrangements in patients with LFS/LFL phenotypes. Two benign tumors were detected in two TP53 mutation carriers: an adrenocortical adenoma and a neurofibroma, which raises a question about the possible implication of TP53 mutations on the development of such lesions.
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Acknowledgments
F. R. V. is a recipient of the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Grant 486599/2012–4 and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) Grant E26/110.535/2012. RCA is recipient of a Ministério da Saúde/Instituto Nacional de Câncer Grant.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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10689_2016_9935_MOESM1_ESM.docx
Online Resource 1 (Supplementary Table 1). Clinical characterization of LFS/LFL probands with no detectable TP53 mutation. (DOCX 20 kb)
10689_2016_9935_MOESM2_ESM.pdf
Online Resource 2 (Supplementary Fig. 1). A) MLPA result of proband #49. B) MLPA result of proband #53. C) Sanger sequencing of exon 8 of TP53 of proband #53; the electropherogram shows the region where the MLPA probe for this exon anneals, showing no sequence variations that could lead to false positive results. (PDF 258 kb)
10689_2016_9935_MOESM3_ESM.docx
Online Resource 3 (Supplementary Table 2). Sensitivity, specificity, and predictive values of the different LFS and LFL diagnostic criteria in our cohort (N = 39). (DOCX 14 kb)
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Andrade, R.C., dos Santos, A.C.E., de Aguirre Neto, J.C. et al. TP53 and CDKN1A mutation analysis in families with Li–Fraumeni and Li–Fraumeni like syndromes. Familial Cancer 16, 243–248 (2017). https://doi.org/10.1007/s10689-016-9935-z
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DOI: https://doi.org/10.1007/s10689-016-9935-z