K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine; Division of Cancer Medicine, Surgery and Transplantation, Department of Oncology, Oslo University Hospital, Oslo;
Clin Cancer Res. 2014 Jul 1;20(13):3569-80. doi: 10.1158/1078-0432.CCR-13-2943. Epub 2014 May 6.
In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC).
TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method.
TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival [HR = 2.03; 95% confidence interval (CI), 1.65-2.48, P < 0.001], and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39-2.49, P < 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in IC1, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive.
This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development.
在乳腺癌中，TP53 基因经常发生突变，这些突变与预后不良有关。不同分子亚型中不同类型的 TP53 突变的预后影响仍知之甚少。在这里，我们根据 PAM50 亚型和整合聚类（IC）来描述 TP53 突变的谱和预后意义。
通过桑格测序法对 METABRIC 队列中的 1420 个肿瘤样本的 TP53 突变状态进行了测序，对所有编码外显子进行了测序。
在 28.3%的肿瘤中发现了 TP53 突变，这导致整体和乳腺癌特异性生存率更差[HR=2.03；95%置信区间（CI），1.65-2.48，P<0.001]，并且在雌激素受体阳性病例中也被发现是预后不良的独立标志物[HR=1.86；95%CI，1.39-2.49，P<0.001]。TP53 的突变谱在乳腺癌亚型之间有所不同，个别改变显示出亚型特异性关联。TP53 突变与 luminal B、HER2 富集和正常样肿瘤患者的死亡率增加有关，但与 luminal A 和基底样肿瘤患者无关。在 ICs 中也观察到了类似的观察结果，其中突变与 IC1、IC4 和 IC5 中较差的预后相关。TP53 突变、TP53 LOH 和 MDM2 扩增对死亡率的综合影响是累加的。
这项研究表明，TP53 突变在乳腺癌的分子亚型中具有不同的临床相关性，并提示 TP53 在乳腺癌发展的生物学中具有不同的作用。
