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. 2025 Jan 3;9(1):pkaf008.
doi: 10.1093/jncics/pkaf008.

Cancer risk in carriers of TP53 germline variants grouped into different functional categories

Lucas John Müntnich  1 , Christina M Dutzmann  1 , Anika Großhennig  2 , Valentina Härter  1 , Myriam Keymling  3 , Angela Mastronuzzi  4 , Emilie Montellier  5 , Juliane Nees  6 , Natalie E Palmaers  1 , Judith Penkert  1   7 , Stefan M Pfister  8 , Tim Ripperger  7 , Sarah Schott  6 , Farina Silchmüller  1 , Pierre Hainaut  5 , Christian P Kratz  1
Affiliations

Cancer risk in carriers of TP53 germline variants grouped into different functional categories

Lucas John Müntnich et al. JNCI Cancer Spectr. .

Abstract

Li-Fraumeni syndrome is a cancer predisposition syndrome caused by pathogenic TP53 germline variants; it is associated with a high lifelong cancer risk. We analyzed the German Li-Fraumeni syndrome registry, which contains data on 304 individuals. Cancer phenotypes were correlated with variants grouped according to their ability to transactivate target genes in a yeast assay using a traditional (nonfunctional, partially functional) and a novel (clusters A, B, and C) classification of variants into different groups. Partially functional and cluster B or C variants were enriched in patients who did not meet clinical testing criteria. Time to first malignancy was longer in carriers of partially functional variants (hazard ratio = 0.38, 95% CI = 0.22 to 0.66). Variants grouped within cluster B (hazard ratio = 0.45, 95% CI = 0.28 to 0.71) or C (hazard ratio = 0.34, 95% CI = 0.19 to 0.62) were associated with later cancer onset than NULL variants. These findings can be used to risk-stratify patients and inform care.

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Conflict of interest statement

None declared.

Figures

Figure 1.
Figure 1.
Spectrum of TP53 variants and statistical genotype-phenotype correlations (updated version of a previous analysis that included 141 patients13). Variant nomenclature refers to reference sequence NM_000546.5. Colored spheres refer to different patients harboring the corresponding variant. The genotype-phenotype correlation was based on assessed Li-Fraumeni spectrum status of individual families and not individual probands. Abbreviations: aLFS = attenuated Li-Fraumeni syndrome; LFS = Li-Fraumeni syndrome.
Figure 2.
Figure 2.
Kaplan-Meier analyses of time to first malignancy in patients stratified according to the results of a yeast assay that measures transactivation of target genes. Left: Traditional classification. Right: Cluster classification.
See this image and copyright information in PMC

References

    1. Li FP, Fraumeni JF. Jr Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747-752. - PubMed
    1. Li FP, Fraumeni JF Jr., Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358-5362. - PubMed
    1. Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233-1238. - PubMed
    1. Srivastava S, Zou ZQ, Pirollo K, et al. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990;348:747-749. - PubMed
    1. Renaux-Petel M, Charbonnier F, Thery JC, et al. Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. J Med Genet. 2018;55:173-180. - PubMed

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