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

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Müntnich, Lucas John | Dutzmann, Christina | Großhennig, Anika | Härter, Valentina | Keymling, Myriam | Mastronuzzi, Angela | Montellier, Emilie | Nees, Juliane | Palmaers, Natalie | Penkert, Judith | Pfister, Stefan | Ripperger, Tim | Schott, Sarah | Silchmüller, Farina | Hainaut, Pierre | Kratz, Christian

Edité par CCSD ; Oxford University Press -

International audience. 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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