Abstract：
In humans, germline TP53 mutations predispose carriers to a wide spectrum of cancers, which is known as Li-Fraumeni syndrome (LFS). To date, the association of melanomas with LFS remains unestablished. No melanomas have been reported in any P53-modified mouse models either. In this study, we show that targeted disruption of P53 at the DNA-binding domain in Xenopus tropicalis recapitulates LFS, with the formation of soft-tissue sarcomas and pancreatic ductal adenocarcinoma. Interestingly, 19% of the 14-month-old tp53Δ7/Δ7 homozygotes and 18% of tp53+/Δ7 heterozygotes spontaneously developed small nevi and non-invasive melanomas. Large invasive melanomas were also observed in other older homozygous mutants, with about 7.9% penetrance. Our data suggest that more dermatologic investigation of LFS patients should be able to settle the association of melanoma with LFS in epidemiology. Our model is also valuable for further investigation of the molecular mechanism underlying melanoma progression upon germline alteration of the tp53 locus.
摘要：
在人类中,种系TP53突变使携带者易患多种癌症，被称为Li-Fraumeni综合征（LFS）。迄今为止,黑素瘤与LFS之间的关联尚未确定.在任何P53修饰的小鼠模型中也没有黑素瘤的报道。在这项研究中,我们表明，在非洲爪狼的DNA结合域P53的靶向破坏概括了LFS，伴有软组织肉瘤和胰腺导管腺癌的形成。有趣的是,19％的14个月大的tp53Δ7/Δ7纯合子和18％的tp53/Δ7杂合子自发发生了小痣和非侵袭性黑素瘤。在其他较老的纯合突变体中也观察到大的侵袭性黑素瘤，外显率约为7.9%。我们的数据表明，对LFS患者进行更多的皮肤病学调查应该能够解决流行病学中黑色素瘤与LFS的关联。我们的模型对于进一步研究tp53基因座种系改变后黑色素瘤进展的分子机制也很有价值。
