Omran Meis, Liu Yaxuan, Sun Zhang Alexander, Poluha Anna, Stenmark-Askmalm Marie, Persson Fredrik, Hallbeck Anna-Lotta, Rosén Anna, Helgadottir Hafdis T, Tham Emma, Bajalica-Lagercrantz Svetlana
Department of Oncology-Pathology, Karolinska Institutet, BioClinicum, SE-171 77, Stockholm, Sweden.
Cancer Theme, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
Eur J Hum Genet. 2025 Apr;33(4):513-522. doi: 10.1038/s41431-024-01753-1. Epub 2025 Jan 5.
We aimed to describe the clinical characteristics of families with heritable TP53-related cancer (hTP53rc) syndrome in Sweden with class 4 and 5 germline TP53 variants (gTP53), and to evaluate the genotype-phenotype correlation. These results were also used to evaluate our previously published phenotype prediction model based on TP53 missense variants and their impact on protein conformation. 90 families with hTP53rc were initially identified in Sweden. After variant reclassification using the TP53-specific ACMG criteria, 83 families remained (176 carriers) to harbour a pathogenic (class 5) or likely pathogenic (class 4) variant in TP53. Of these, 112 carriers (64%) had a previous history of cancer, and 35 (31%) had developed more than one primary tumour. 16% of the families met the stricter criteria for Classic Li-Fraumeni syndrome, 45% the updated Chompret criteria, 35% for hereditary breast cancer (HBC), and the remaining 5% were classified as "Others". We identified 42 different gTP53 variants of which 22 were missense. The most frequently observed variant was the missense c.542 G > A, p.R181H identified in 14/29 (48%) of HBC families. Fifteen of the 20 informative missense variants (75%) were phenotypically predicted correctly using our previously published in silico prediction model. The TP53 p.R181H was identified as a common Swedish variant predominantly associated with an HBC phenotype. Apart from this variant, there were no significant genotype-phenotype correlations. Therefore, due to phenotypic overlap it is still too early to stratify surveillance programme for different TP53-carriers.
我们旨在描述瑞典携带4类和5类种系TP53变异（gTP53）的遗传性TP53相关癌症（hTP53rc）综合征家庭的临床特征，并评估基因型与表型的相关性。这些结果还用于评估我们之前发表的基于TP53错义变异及其对蛋白质构象影响的表型预测模型。最初在瑞典确定了90个hTP53rc家庭。使用TP53特异性的美国医学遗传学与基因组学学会（ACMG）标准对变异进行重新分类后，83个家庭（176名携带者）仍携带TP53中的致病性（5类）或可能致病性（4类）变异。其中，112名携带者（64%）有癌症病史，35名（31%）发生了不止一种原发性肿瘤。16%的家庭符合经典李-弗劳梅尼综合征更严格的标准，45%符合更新后的乔普雷标准，35%符合遗传性乳腺癌（HBC）标准，其余5%被归类为“其他”。我们鉴定出42种不同的gTP53变异，其中22种是错义变异。最常观察到的变异是错义c.542 G > A，p.R181H，在14/29（48%）的HBC家庭中被鉴定出来。使用我们之前发表的计算机预测模型，20个信息性错义变异中有15个（75%）的表型预测正确。TP53 p.R181H被鉴定为主要与HBC表型相关的常见瑞典变异。除了这个变异外，没有显著的基因型与表型相关性。因此，由于表型重叠，针对不同TP53携带者分层监测计划仍为时过早。
