A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients
A comparison between p53 accumulation determined by immunohistochemistry and TP53 mutations as prognostic variables in tumours from breast cancer patients
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DOI：
10.1080/02841860802047411
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发表时间：
2008-01-01
期刊：
影响因子：
3.1
通讯作者：
Overgaard, Jens
中科院分区：
文献类型：
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作者：
Alsner, Jan;Jensen, Vibeke;Overgaard, Jens
背景p53积累和TP 53突变是乳腺癌的已知预后标志物。为了阐明它们之间的相互关系以及不同TP 53突变类型的重要性，我们在630例乳腺癌患者的肿瘤中研究了这些标记物。材料和方法。对肿瘤切片进行p53染色，并基于染色强度和具有核染色的侵袭性肿瘤细胞的百分比进行评分。通过测序鉴定TP 53突变。患者队列来自DBCG（丹麦乳腺癌合作组）方案DBCG 82和DBCG 89。结果TP 53在29%的患者中发生突变。在15年的随访中，直接参与DNA或锌结合的错义突变患者的疾病特异性生存率（DSS）为21 +/-8%。在结构/保守结构域中具有剩余错义突变的患者和具有无效突变的患者的DSS分别为36+/-6%和31+/-17%。对于没有TP 53突变的患者和具有影响这些结构域之外的氨基酸的突变的患者，15年DSS分别为51+/-3%和71+/-10%。在567例患者中成功地对p53积累进行评分，并将其分为三组。没有p53表达的肿瘤具有高频率的无效突变（37%，而整个队列中为10%），并且具有高p53表达的肿瘤在结构/保守结构域内包含82%的错义突变，包括直接参与DNA或锌结合的那些。结论乳腺癌患者的临床结果对于不同的TP 53突变类型是显著不同的，但需要进一步的功能研究来阐明这些突变类型的确切作用。大多数导致突变型p53蛋白积聚的突变可以通过免疫组织化学检测到，但特异性低。显示缺乏可检测的p53蛋白的样品应被视为可能的无效突变的指示。
Background. p53 accumulation and TP53 mutations are known prognostic markers for breast cancer. To clarify their interrelationship and the importance of different TP53 mutation types, these markers were investigated in tumours; from 630 patients with breast cancer. Materials and methods. Tumour sections were stained for p53 and scored based on staining intensity and percentages of invasive tumour cells with nuclear staining. TP53 mutations were identified by sequencing. Patient cohorts were from the DBCG (Danish Breast Cancer Cooperative Group) protocols DBCG82 and DBCG89. Results. TP53 was mutated in 29% of the patients. The disease-specific survival (DSS) at 15 years of follow-up for patients with missense mutations directly involved in DNA or zinc binding was 21 +/- 8%. Patients with the remaining missense mutations within the structural/conserved domains and patients with null mutations had a DSS of 36+/-6% and 31+/-17%, respectively. For patients without TP53 mutations and patients with mutations affecting amino acids outside these domains, the 15 year DSS was 51+/-3% and 71+/-10%, respectively. p53 accumulation was successfully scored in 567 patients and categorized into three groups. Tumours with no p53 expression had a high frequency of null mutations (37% compared to 10% in the whole cohort), and tumours with high p53 expression contained 82% of the missense mutations inside structural/conserved domains including those directly involved in DNA or zinc binding. Conclusion. The clinical outcome for breast cancer patients is significantly different for different TP53 mutation types, but further functional studies are required to clarify the exact role of these mutation types. Most of the mutations that lead to mutant p53 protein accumulation can be detected by immunohistochemistry but the specificity is low. Samples showing lack of detectable p53 protein should be considered as an indication of a possible null mutation.