Functional characterization of novel germline TP53 variants in Swedish families
Functional characterization of novel germline TP53 variants in Swedish families
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DOI：
10.1111/cge.13564
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发表时间：
2019-09-01
影响因子：
3.5
通讯作者：
Bajalica-Lagercrantz, Svetlana
中科院分区：
文献类型：
--
作者：
Kharaziha, Pedram;Ceder, Sophia;Bajalica-Lagercrantz, Svetlana
致病性生殖系TP 53变体易患广泛的早发性癌症，通常被认为是Li-Fraumeni综合征（LFS）。它们也在1%的遗传性乳腺癌（HrBC）家族中被发现，这些家族不符合LFS的标准。在这项研究中，我们提出了在31个瑞典LFS或HrBC家庭中鉴定的24种不同的TP 53变体。其中10个变异，9个外显子和1个剪接，以前没有被描述为生殖系致病性变异。九个外显子变体的功能特征，并证明部分反式激活活性相比，野生型p53。一些显示类似于野生型p53的核定位，而另一些具有细胞质或核周定位。4个移码突变体（W 91 Gfs *32、L111 Wfs*12、S227 Lfs*20和S240 Kfs *25）的p53活性可忽略不计，而F134 L和T231 del的p53活性较低。L111 Wfs*12和T231 del变体也缺乏诱导细胞凋亡。错义变体R110 C保留p53效应，无义E349* 显示至少部分转录因子活性，但具有降低的触发细胞凋亡的能力。这是在瑞典队列中首次对新型生殖系TP 53致病性或可能致病性变体进行功能表征，以试图了解其分别与LFS和HrBC的相关性。
Pathogenic germline TP53 variants predispose to a wide range of early onset cancers, often recognized as the Li-Fraumeni syndrome (LFS). They are also identified in 1% of families with hereditary breast cancer (HrBC) that do not fulfill the criteria for LFS. In this study, we present a total of 24 different TP53 variants identified in 31 Swedish families with LFS or HrBC. Ten of these variants, nine exonic and one splice, have previously not been described as germline pathogenic variants. The nine exonic variants were functionally characterized and demonstrated partial transactivation activity compared to wild-type p53. Some show nuclear localization similar to wild-type p53 while others possess cytoplasmic or perinuclear localization. The four frameshift variants (W91Gfs*32, L111 Wfs*12, S227 Lfs*20 and S240Kfs*25) had negligible, while F134 L and T231del had low level of p53 activity. The L111 Wfs*12 and T231del variants are also deficient for induction of apoptosis. The missense variant R110C retain p53 effects and the nonsense E349* shows at least partial transcription factor activity but has reduced ability to trigger apoptosis. This is the first functional characterization of novel germline TP53 pathogenic or likely pathogenic variants in the Swedish cohort as an attempt to understand its association with LFS and HrBC, respectively.