Fitarelli-Kiehl Mariana, Giacomazzi Juliana, Santos-Silva Patricia, Graudenz Marcia Silveira, Palmero Edenir Inez, Michelli Rodrigo Augusto Depieri, Achatz Maria Isabel, de Toledo Osório Cynthia Aparecida Bueno, de Faria Ferraz Victor Evangelista, Picanço Clarissa Gondim, Ashton-Prolla Patricia
Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil,
Fam Cancer. 2015 Jun;14(2):333-6. doi: 10.1007/s10689-015-9779-y.
Germline TP53 mutations are associated with Li-Fraumeni syndrome, an autosomal dominant disorder characterized by a predisposition to multiple early-onset cancers including breast cancer (BC), the most prevalent tumor among women. The majority of germline TP53 mutations are clustered within the DNA-binding domain of the gene, disrupting the structure and function of the protein. A specific germline mutation in the tetramerization domain of p53, p.R337H, was reported at a high frequency in Southern and Southeastern Brazil. This mutation appears to result in a more subtle defect in the protein, which becomes functionally deficient only under particular conditions. Recent studies show that the BC phenotype in TP53 mutation carriers is often HER2 positive (63-83%). Considering that the immunophenotype of BC among p.R337H carriers has not been reported, we reviewed immunohistochemistry data of 66 p.R337H carriers in comparison with 12 patients with other non-functional TP53 germline mutation. Although 75% of carriers of these mutations showed significant HER2 overexpression (3+), corroborating previous studies, only 22.7% of p.R337H patients had BC overexpressing HER2. These results reinforce the notion that different germline mutations in TP53 may predispose to BC via different mechanisms.
种系TP53突变与李-佛美尼综合征相关，这是一种常染色体显性疾病，其特征是易患多种早发性癌症，包括乳腺癌（BC），乳腺癌是女性中最常见的肿瘤。大多数种系TP53突变聚集在该基因的DNA结合域内，破坏了蛋白质的结构和功能。在巴西南部和东南部，p53四聚化结构域中的一种特定种系突变p.R337H被高频报道。这种突变似乎导致蛋白质中更细微的缺陷，该蛋白质仅在特定条件下功能才会出现缺陷。最近的研究表明，TP53突变携带者中的BC表型通常为HER2阳性（63%-83%）。鉴于尚未报道p.R337H携带者中BC的免疫表型，我们回顾了66例p.R337H携带者的免疫组化数据，并与12例携带其他无功能TP53种系突变的患者进行了比较。尽管这些突变的75%携带者显示出显著的HER2过表达（3+），这与之前的研究结果一致，但只有22.7%的p.R337H患者的BC过表达HER2。这些结果强化了这样一种观点，即TP53中的不同种系突变可能通过不同机制导致BC。
