Monti Paola, Ciribilli Yari, Jordan Jennifer, Menichini Paola, Umbach David M, Resnick Michael A, Luzzatto Lucio, Inga Alberto, Fronza Gilberto
Molecular Mutagenesis Unit, Department of Translational Oncology, National Cancer Research Institute, Genoa, Italy.
Clin Cancer Res. 2007 Jul 1;13(13):3789-95. doi: 10.1158/1078-0432.CCR-06-2545.
The TP53 tumor suppressor gene encodes a sequence-specific transcription factor that is able to transactivate several sets of genes, the promoters of which include appropriate response elements. Although human cancers frequently contain mutated p53, the alleles as well as the clinical expression are often heterogeneous. Germ line mutations of TP53 result in cancer proneness syndromes known as Li-Fraumeni, Li-Fraumeni--like, and nonsyndromic predisposition with or without family history. p53 mutants can be classified as partial deficiency alleles or severe deficiency alleles depending on their ability to transactivate a set of human target sequences, as measured using a standardized yeast-based assay (see http://www.umd.be:2072/index.html). We have investigated the extent to which the functional features of p53 mutant alleles determine clinical features in patients who have inherited these alleles and have developed cancer.
We retrieved clinical data from the IARC database (see http://www.p53.iarc.fr/Germline.html) for all cancer patients with germ line p53 mutations and applied stringent statistical evaluations to compare the functional classification of p53 alleles with clinical phenotypes.
Our analyses reveal that partial deficiency alleles are associated with a milder family history (P = 0.007), a lower numbers of tumors (P = 0.007), and a delayed disease onset (median, 31 versus 15 years; P = 0.007) which could be related to distinct tumor spectra.
These findings establish for the first time significant correlations between the residual transactivation function of individual TP53 alleles and clinical variables in patients with inherited p53 mutations who develop cancer.
TP53肿瘤抑制基因编码一种序列特异性转录因子，该因子能够反式激活几组基因，这些基因的启动子包含适当的反应元件。尽管人类癌症中经常存在p53突变，但等位基因以及临床表型往往是异质性的。TP53的种系突变会导致患癌倾向综合征，如李-弗劳梅尼综合征、类李-弗劳梅尼综合征以及有无家族病史的非综合征性易感性。根据使用标准化酵母检测法（见http://www.umd.be:2072/index.html）测量的反式激活一组人类靶序列的能力，p53突变体可分为部分缺陷等位基因或严重缺陷等位基因。我们研究了p53突变等位基因的功能特征在多大程度上决定了继承这些等位基因并患癌的患者的临床特征。
我们从国际癌症研究机构数据库（见http://www.p53.iarc.fr/Germline.html）中检索了所有患有种系p53突变的癌症患者的临床数据，并应用严格的统计评估来比较p53等位基因的功能分类与临床表型。
我们的分析表明，部分缺陷等位基因与较轻的家族病史（P = 0.007）、较少的肿瘤数量（P = 0.007）以及疾病发病延迟（中位数，31岁对15岁；P = 0.007）相关，这可能与不同的肿瘤谱有关。
这些发现首次在患癌的遗传性p53突变患者中建立了个体TP53等位基因的残余反式激活功能与临床变量之间的显著相关性。
