Müntnich Lucas John, Dutzmann Christina M, Großhennig Anika, Härter Valentina, Keymling Myriam, Mastronuzzi Angela, Montellier Emilie, Nees Juliane, Palmaers Natalie E, Penkert Judith, Pfister Stefan M, Ripperger Tim, Schott Sarah, Silchmüller Farina, Hainaut Pierre, Kratz Christian P
Pediatric Hematology and Oncology, Hannover Medical School, 30625 Hannover, Germany.
Institute of Biostatistics, Hannover Medical School, 30625 Hannover, Germany.
JNCI Cancer Spectr. 2025 Jan 3;9(1). doi: 10.1093/jncics/pkaf008.
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.
李-弗劳梅尼综合征是一种由致病性TP53种系变异引起的癌症易感综合征；它与终生患癌风险高相关。我们分析了德国李-弗劳梅尼综合征登记处的数据，其中包含304人的数据。癌症表型与根据变异体在酵母试验中激活靶基因的能力分组的变异体相关，变异体采用传统（无功能、部分功能）和新的（A、B和C组）分类方法分为不同组。部分功能变异体以及B组或C组变异体在不符合临床检测标准的患者中更为富集。部分功能变异体携带者首次发生恶性肿瘤的时间更长（风险比=0.38，95%置信区间=0.22至0.66）。与无功能变异体相比，B组（风险比=0.45，95%置信区间=0.28至0.71）或C组（风险比=0.34，95%置信区间=0.19至0.62）分组的变异体与癌症发病较晚相关。这些发现可用于对患者进行风险分层并指导治疗。
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